Unsaturated nitrogen heterocyclic compounds useful as pde10 inhibitors

ABSTRACT

Unsaturated nitrogen heterocyclic compounds of formula (I): 
     
       
         
         
             
             
         
       
     
     as defined in the specification, compositions containing them, and processes for preparing such compounds. Provided herein also are methods of treating disorders or diseases treatable by inhibition of PDE10, such as obesity, Huntington&#39;s Disease, non-insulin dependent diabetes, schizophrenia, bipolar disorder, obsessive-compulsive disorder, and the like.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional Application No.61/334,525, filed May 13, 2010, which is hereby incorporated byreference.

FIELD OF THE INVENTION

Provided herein are certain unsaturated nitrogen heterocyclic compoundsthat are PDE10 inhibitors, pharmaceutical compositions containing suchcompounds, and processes for preparing such compounds. Provided hereinalso are methods of treating disorders or diseases treatable byinhibition of PDE10, such as obesity, Huntington's disease, non-insulindependent diabetes, schizophrenia, bipolar disorder,obsessive-compulsive disorder, and the like.

BACKGROUND

Neurotransmitters and hormones, as well as other types of extracellularsignals such as light and odors, create intracellular signals byaltering the amounts of cyclic nucleotide monophosphates (cAMP and cGMP)within cells. These intracellular messengers alter the functions of manyintracellular proteins. Cyclic AMP regulates the activity ofcAMP-dependent protein kinase (PKA). PKA phosphorylates and regulatesthe function of many types of proteins, including ion channels, enzymes,and transcription factors. Downstream mediators of cGMP signaling alsoinclude kinases and ion channels. In addition to actions mediated bykinases, cAMP and cGMP bind directly to some cell proteins and directlyregulate their activities.

Cyclic nucleotides are produced from the actions of adenylyl cyclase andguanylyl cyclase, which convert ATP to cAMP and GTP to cGMP.Extracellular signals, often through the actions of G protein-coupledreceptors, regulate the activities of the cyclases. Alternatively, theamount of cAMP and cGMP may be altered by regulating the activities ofthe enzymes that degrade cyclic nucleotides. Cell homeostasis ismaintained by the rapid degradation of cyclic nucleotides afterstimulus-induced increases. The enzymes that degrade cyclic nucleotidesare called 3′,5′-cyclic nucleotide-specific phosphodiesterases (PDEs).

Eleven PDE gene families (PDE1-PDE11) have been identified based ontheir distinct amino acid sequences, catalytic and regulatorycharacteristics, and sensitivity to small molecule inhibitors. Thesefamilies are coded for by 21 genes; and further multiple splice variantsare transcribed from many of these genes. Expression patterns of each ofthe gene families are distinct. PDEs differ with respect to theiraffinity for cAMP and cGMP. Activities of different PDEs are regulatedby different signals. For example, PDE1 is stimulated byCa²⁺/calmodulin. PDE2 activity is stimulated by cGMP. PDE3 is inhibitedby cGMP. PDE4 is cAMP specific and is specifically inhibited byrolipram. PDE5 is cGMP-specific. PDE6 is expressed in retina.

PDE10 sequences were identified by using bioinformatics and sequenceinformation from other PDE gene families (Fujishige et al., J. Biol.Chem. 274:18438-18445, 1999; Loughney et al., Gene 234:109-117, 1999;Soderling et al., Proc. Natl. Acad. Sci. USA 96:7071-7076, 1999). ThePDE10 gene family is distinguished based on its amino acid sequence,functional properties and tissue distribution. The human PDE10 gene islarge, over 200 kilobases, with up to 24 exons coding for each of thesplice variants. The amino acid sequence is characterized by two GAFdomains (which bind cGMP), a catalytic region, and alternatively splicedN and C termini. Numerous splice variants are possible because at leastthree alternative exons encode N termini and two exons encode C-termini.PDE10A1 is a 779 amino acid protein that hydrolyzes both cAMP and cGMP.The K_(m) values for cAMP and cGMP are 0.05 and 3.0 micromolar,respectively. In addition to human variants, several variants with highhomology have been isolated from both rat and mouse tissues and sequencebanks.

PDE10 RNA transcripts were initially detected in human testis and brain.Subsequent immunohistochemical analysis revealed that the highest levelsof PDE10 are expressed in the basal ganglia. Specifically, striatalneurons in the olfactory tubercle, caudate nucleus and nucleus accumbensare enriched in PDE10. Western blots did not reveal the expression ofPDE10 in other brain tissues, although immunoprecipitation of the PDE10complex was possible in hippocampal and cortical tissues. This suggeststhat the expression level of PDE10 in these other tissues is 100-foldless than in striatal neurons. Expression in hippocampus is limited tothe cell bodies, whereas PDE10 is expressed in terminals, dendrites andaxons of striatal neurons.

The tissue distribution of PDE10 indicates that PDE10 inhibitors can beused to raise levels of cAMP and/or cGMP within cells that express thePDE10 enzyme, for example, in neurons that comprise the basal gangliaand therefore would be useful in treating a variety of neuropsychiatricconditions involving the basal ganglia such as obesity, non-insulindependent diabetes, schizophrenia, bipolar disorder, obsessivecompulsive disorder, and the like.

Noninvasive, nuclear imaging techniques can be used to obtain basic anddiagnostic information about the physiology and biochemistry of avariety of living subjects including experimental animals, normal humansand patients. These techniques rely on the use of sophisticated imaginginstrumentation that is capable of detecting radiation emitted fromradiotracers administered to such living subjects. The informationobtained can be reconstructed to provide planar and tomographic imagesthat reveal distribution of the radiotracer as a function of time. Useof appropriately designed radiotracers can result in images whichcontain information on the structure, function and most importantly, thephysiology and biochemistry of the subject. Much of this informationcannot be obtained by other means. The radiotracers used in thesestudies are designed to have defined behaviors in vivo which permit thedetermination of specific information concerning the physiology orbiochemistry of the subject or the effects that various diseases ordrugs have on the physiology or biochemistry of the subject. Currently,radiotracers are available for obtaining useful information concerningsuch things as cardiac function, myocardial blood flow, lung perfusion,liver function, brain blood flow, regional brain glucose and oxygenmetabolism.

Compounds of the invention can be labeled with either positron or gammaemitting radionuclides. For imaging, the most commonly used positronemitting (PET) radionuclides are ¹¹C, ¹⁸F, ¹⁵O, ¹³N, ⁷⁶Br, ⁷⁷Br, ¹²³I,or ¹²⁵I, wherein ¹¹C, ¹⁸F, ¹²³I, or ¹²⁵I are preferred, all of which areaccelerator produced. In the two decades, one of the most active areasof nuclear medicine research has been the development of receptorimaging radiotracers. These tracers bind with high affinity andspecificity to selective receptors and neuroreceptors. For example,Johnson and Johnson has synthesized and evaluated ¹⁸F-JNJ41510417 as aselective and high-affinity radioligand for in vivo brain imaging ofPDE10A using PET (The Journal Of Nuclear Medicine; Vol. 51; No. 10;October 2010).

SUMMARY OF THE INVENTION

The present invention comprises a new class of unsaturated nitrogenheterocyclic compounds useful in the treatment of diseases, such asPDE10-mediated diseases and other maladies, such as schizophrenia,Huntington's disease, bipolar disorder, or obsessive-compulsivedisorder. Accordingly, the invention also comprises pharmaceuticalcompositions comprising the compounds, methods for the treatment ofPDE10-mediated diseases and other maladies, such as schizophrenia,Huntington's disease, bipolar disorder, or obsessive-compulsivedisorder, using the compounds and compositions of the invention, andintermediates and processes useful for the preparation of the compoundsof the invention.

Another aspect of the invention comprises a new class of unsaturatednitrogen heterocyclic compounds radiolabeled with a positron emittingradionuclide selected from ¹¹C, ¹⁸F, ¹⁵O, ¹³N, ⁷⁶Br, ⁷⁷Br, ¹²³I, or¹²⁵I, a radiopharmaceutical composition comprising the radiolabelledcompound, a method for the diagnostic imaging of PDE10 receptors in amammal, including human, or tissues bearing PDE10 receptors in a mammal,including human brain, which comprises administering to a mammal in needof such diagnostic imaging an effective amount of the radiolabeledcompound, and a method for the detection or quantification of PDE10receptors in mammalian tissue, including human tissue, which comprisescontacting such mammalian tissue in which such detection orquantification is desired with an effective amount of the radiolabeledcompound.

The compounds of the invention are represented by the following generalstructure:

or a pharmaceutically acceptable salt thereof, wherein m, p, q, R¹,R^(4a), R^(4b), R⁵, Y, X¹, X², X³, X⁴, and X⁵ are defined below.

The compounds of the invention are represented by the following generalstructure:

or a pharmaceutically acceptable salt thereof, wherein m, p, q, R^(4a),R^(4b), R⁵, Y, X¹, X², X³, and X⁴ are defined below.

The compounds of the invention are represented by the following generalstructure:

or a pharmaceutically acceptable salt thereof, wherein m, p, q, R¹, R²,R³, R^(4a), R^(4b), R⁵, Y, and X¹ are defined below.

Other compounds of the invention are represented by the followinggeneral structure:

or a pharmaceutically acceptable salt thereof, wherein m, p, q, Ring D,R², R³, R^(4a), R^(4b), R⁵, Y, and X¹ are defined below.

DETAILED DESCRIPTION OF THE INVENTION

One aspect of the current invention relates to compounds having thegeneral structure of formula (I):

or a pharmaceutically acceptable salt thereof, wherein:

X¹ is N or CR⁶;

X² is N or CR²;

X³ is N or CR³;

X⁴ is N or CR⁶;

X⁵ is N or CR⁶;

wherein 1 to 2 of X¹, X², X³, X⁴ and X⁵ are N;

R¹ is halo, C₁₋₈alk, C₁₋₄haloalk, —OR^(c), —N(R^(a))C(═O)R^(b),—C(═O)R^(a), —C(═O)R^(c), —C(═O)—R^(a), —NR^(a)R^(c),—N(R^(c))C(═O)R^(b), —N(R^(a))C(═O)R^(c), —C(═O)NR^(a)R^(b),—C(═O)NR^(a)R^(c), or C₀₋₄alk-L¹; wherein said C₁₋₈alk group issubstituted by 0, 1, 2 or 3 groups which are halo, C₁₋₃haloalk, —OH,—OC₁₋₄alk, —NH₂, —NHC₁₋₄alk, —OC(═O)C₁₋₄alk, or —N(C₁₋₄alk)C₁₋₄alk;

Y is a C₀₋₄alk, —C(═O), SO, or SO₂;

each R² and R³ is independently R¹, H, halo, CN, OH, —OC₁₋₄alk, C₁₋₄alk,C₁₋₄haloalk, —C₁₋₆alkOR^(a), —C(═O)C₁₋₄alk, —C(═O)NR^(a)R^(a),—C₀₋₄alkNH—C(═O)R^(a), or R^(c);

or alternatively the ring containing X¹, X², X³, X⁴ and X⁵ can be fusedto ring A, ring B, or ring C; having the formula:

wherein said ring A, ring B, or ring C is a fused 4- to6-membered-saturated, -partially saturated, or -unsaturated-carbocyclicor -heterocyclic ring containing 0, 1, 2, or 3 heteroatoms; and issubstituted by 0, 1, or 2 R¹⁰ groups;

R^(4a) is H, OH, halo, C₁₋₄alk, or C₁₋₄haloalk;

R^(4b) is halo, CN, OH, OC₁₋₄alk, C₁₋₄alk, C₁₋₄haloalk, or oxo;

R⁵ is —C₁₋₆alkOR^(a), 5- to 6-membered heteroaryl, unsaturated 9- to10-membered bicyclo-heterocyclic ring, or 11- to 15-memberedtricyclo-heterocyclic ring; R⁵ ring is substituted by 0, 1, 2, 3, or 4R⁸ groups;

R⁶ is independently R¹, H, halo, CN, OH, OC₁₋₄alk, C₁₋₄alk orC₁₋₄haloalk;

m is 0, 1, 2, 3, or 4;

each of p and q is independently 0, 1, 2, 3, 4, 5, or 6; wherein the sumof p and q is 2 to 6;

the ring containing p and q contains 0, 1, or 2 double bonds;

R^(a) is independently H or R^(b);

R^(b) is independently phenyl, benzyl, or C₁₋₆alk, wherein said phenyl,benzyl, and C₁₋₆alk are substituted by 0, 1, 2 or 3 substituents whichare, independently, halo, C₁₋₄alk, C₁₋₃haloalk, —OH, —OC₁₋₄alk, —NH₂,—NHC₁₋₄alk, —OC(═O)C₁₋₄alk, or —N(C₁₋₄alk)C₁₋₄alk;

R^(c) is C₀₋₄alk-L²;

each L¹ is independently a carbon-linked or nitrogen-linked saturated,partially-saturated or unsaturated 3-, 4-, 5-, 6-, or 7-memberedmonocyclic ring or a saturated, partially-saturated or unsaturated 6-,7-, 8-, 9-, 10-, 11-, or 12-membered bicyclic ring, said ring contains0, 1, 2, 3, or 4 N atoms and 0, 1, or 2 atoms which are O or S; L¹ isindependently substituted by 0, 1, 2 or 3 R⁹ groups;

each L² is independently a carbon-linked or nitrogen-linked saturated,partially-saturated or unsaturated 3-, 4-, 5-, 6-, or 7-memberedmonocyclic ring or a saturated, partially-saturated or unsaturated 6-,7-, 8-, 9-, 10-, 11-, or 12-membered bicyclic ring, said ring contains0, 1, 2, 3, or 4 N atoms and 0, 1, or 2 atoms which are O or S; L² isindependently substituted by 0, 1, 2 or 3 R¹¹ groups;

R⁸ is halo, CN, OH, OC₁₋₄alk, C₁₋₄alk, C₁₋₄haloalk, OC₁₋₄haloalk,—C(═O)R^(b), —C(═O)R^(c), —C(═O)NHR^(b), —C(═O)NHR^(c), —S(═O)₂R^(b),—S(═O)₂R^(c), —S(═O)₂NR^(a)R^(a), R^(b), R^(c), NO₂, OR^(b), or OR^(c);

R⁹ is halo, C₁₋₆alk, C₁₋₄haloalk, —OR^(a), —OC₁₋₄haloalk, CN,—C(═O)R^(b), —C(═O)OR^(a), —C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a),—OC(═O)R^(b), —OC(═O)NR^(a)R^(a), —OC₁₋₆alkNR^(a)R^(a), —OC₁₋₆alkOR^(a),—SR^(a), —S(═O)R^(b), —S(═O)₂R^(b), —S(═O)₂NR^(a)R^(a), —NR^(a)R^(a),—N(R^(a))C(═O)R^(b), —N(R^(a))C(═O)OR^(b), —N(R^(a))C(═O)NR^(a)R^(a),—N(R^(a))C(═NR^(a))NR^(a)R^(a), —N(R^(a))S(═O)₂R^(b),—N(R^(a))S(═O)₂NR^(a)R^(a), —NR^(a)C₁₋₆alkNR^(a)R^(a),—NR^(a)C₁₋₆alkOR^(a), —C₁₋₆alkNR^(a)R^(a), —C₁₋₆alkOR^(a),—C₁₋₆alkN(R^(a))C(═O)R^(b), —C₁₋₆alkOC(═O)R^(b),—C₁₋₆alkC(═O)NR^(a)R^(a), —C₁₋₆alkC(═O)OR^(a), oxo, or R^(c);

R¹⁰ is oxo, C₁₋₆alk, C₁₋₃haloalk, —OH, —OC₁₋₄alk, —NH₂, —NHC₁₋₄alk,—OC(═O)C₁₋₄alk, or —N(C₁₋₄alk)C₁₋₄alk; and

R¹¹ is halo, C₁₋₆alk, C₁₋₄haloalk, —OR^(a), —OC₁₋₄haloalk, CN,—C(═O)R^(b), —C(═O)OR^(a), —C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a),—OC(═O)R^(b), —OC(═O)NR^(a)R^(a), —OC₁₋₆alkNR^(a)R^(a), —OC₁₋₆alkOR^(a),—SR^(a), —S(═O)R^(b), —S(═O)₂R^(b), —S(═O)₂NR^(a)R^(a), —NR^(a)R^(a),—N(R^(a))C(═O)R^(b), —N(R^(a))C(═O)OR^(b), —N(R^(a))C(═O)NR^(a)R^(a),—N(R^(a))C(═NR^(a))NR^(a)R^(a), —N(R^(a))S(═O)₂R^(b),—N(R^(a))S(═O)₂NR^(a)R^(a), —NR^(a)C₁₋₆alkNR^(a)R^(a),—NR^(a)C₁₋₆alkOR^(a), —C₁₋₆alkNR^(a)R^(a), —C₁₋₆alkOR^(a),—C₁₋₆alkN(R^(a))C(═O)R^(b), —C₁₋₆alkOC(═O)R^(b),—C₁₋₆alkC(═O)NR^(a)R^(a), —C₁₋₆alkC(═O)OR^(a), or oxo.

In one embodiment of the compound of formula (I), (II), (III), or (IV),or a pharmaceutically acceptable salt thereof, the group

In another embodiment of the compound of formula (I), (II), (III), or(IV), or a pharmaceutically acceptable salt thereof, the group

In another embodiment of the compound of formula (I), (II), (III), or(IV), or a pharmaceutically acceptable salt thereof, each of said RingA, Ring B, and Ring C is a fused 4- to 6-membered-saturated, -partiallysaturated, or -unsaturated-carbocyclic which are fused phenyl,cyclobutyl, cyclopentyl, or cyclohexyl; said Ring A, Ring B, and Ring Cis substituted by 0, 1, or 2 R¹⁰ groups which are oxo, C₁₋₆alk,C₁₋₃haloalk, —OH, —OC₁₋₄alk, —NH₂, —NHC₁₋₄alk, —OC(═O)C₁₋₄alk, or—N(C₁₋₄alk)C₁₋₄alk.

In another embodiment of the compound of formula (I), (II), (III), or(IV), or a pharmaceutically acceptable salt thereof, each of said RingA, Ring B, and Ring C is a fused 5-membered-saturated, -partiallysaturated, or -unsaturated-heterocyclic ring which are fused furanyl,thiophenyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, dioxolanyl, oxazolyl,thiazolyl, isothiazolyl, imidazolyl, imidazolinyl, imidazolidinyl,pyrazolyl, pyrazolinyl, pyrazolidinyl, isoxazolyl, or isothiazolyl; saidRing A, Ring B, and Ring C is substituted by 0, 1, or 2 R¹⁰ groups whichare oxo, C₁₋₆alk, C₁₋₃haloalk, —OH, —OC₁₋₄alk, —NH₂, —NHC₁₋₄alk,—OC(═O)C₁₋₄alk, or —N(C₁₋₄alk)C₁₋₄alk.

In another embodiment of the compound of formula (I), (II), (III), or(IV), or a pharmaceutically acceptable salt thereof, each of said RingA, Ring B, and Ring C is a fused 6-membered-saturated, -partiallysaturated, or -unsaturated-heterocyclic ring which are fused pyranyl,pyridinyl, piperidinyl, dioxanyl, morpholinyl, dithianyl,thiomorpholinyl, pyridazinyl, pyrazinyl, or piperazinyl; said Ring A,Ring B, and Ring C is substituted by 0, 1, or 2 R¹⁰ groups which areoxo, C₁₋₆alk, C₁₋₃haloalk, —OH, —OC₁₋₄alk, —NH₂, —NHC₁₋₄alk,—OC(═O)C₁₋₄alk, or —N(C₁₋₄alk)C₁₋₄alk.

In another embodiment of the compound of formula (I), (II), (III), or(IV), or a pharmaceutically acceptable salt thereof, each of p and q isindependently 1.

In another embodiment of the compound of formula (I), (II), (III), or(IV), or a pharmaceutically acceptable salt thereof, each of p and q isindependently 2.

In another embodiment of the compound of formula (I), (II), (III), or(IV), or a pharmaceutically acceptable salt thereof, the ring containingp and q contains 0 or 1 double bond.

In another embodiment of the compound of formula (I), (II), (III), or(IV), or a pharmaceutically acceptable salt thereof, wherein the sum ofp and q is 3; and the ring containing p and q contains 0 or 1 doublebond.

In another embodiment of the compound of formula (I), (II), (III), or(IV), or a pharmaceutically acceptable salt thereof, R^(4b) is oxo and mis 1.

In another embodiment of the compound of formula (I), (II), (III), or(IV), or a pharmaceutically acceptable salt thereof, R⁵ is unsaturated10-membered bicyclo-heterocyclic ring; wherein each R⁵ ring issubstituted by 0, 1, or 2 R⁸ groups.

In another embodiment of the compound of formula (I), (II), (III), or(IV), or a pharmaceutically acceptable salt thereof, the group

wherein each

is substituted by 0, 1, or 2 R¹⁰ groups.

In another embodiment of the compound of formula (I), (II), (III), or(IV), or a pharmaceutically acceptable salt thereof, m is 1 or 2.

In another embodiment of the compound of formula (I), (II), (III), or(IV), or a pharmaceutically acceptable salt thereof, m is 0.

In another embodiment of the compound of formula (I), (II), (III), or(IV), or a pharmaceutically acceptable salt thereof, R¹ is —NR^(a)R^(c),—OR^(c) or —C₀₋₄alk-L¹.

In another embodiment of the compound of formula (I), (II), (III), or(IV), or a pharmaceutically acceptable salt thereof, L¹ is acarbon-linked-saturated or partially-saturated 3-, 4-, 5-, 6-, or7-membered monocyclic ring, wherein each said ring contains 0, 1, or 2 Natoms and 0 or 1 O atoms, and wherein each said L¹ is substituted by 0,1 or 2 R⁹ groups which are F, Cl, Br, C₁₋₆alk, —OR^(a), CN, —C(═O)R^(b),C(═O)OR^(a), —C(═O)NR^(a)R^(a), —SR^(a), —S(═O)R^(b), —S(═O)₂R^(b),—NR^(a)R^(a), —N(R^(a))C(═O)R^(b), —N(R^(a))C(═O)OR^(b), —C₁₋₆alkOR^(a),—C₁₋₆alkN(R^(a))C(═O)R^(b), —C₁₋₆alkOC(═O)R^(b),—C₁₋₆alkC(═O)NR^(a)R^(a), —C₁₋₆alkC(═O)OR^(a), oxo, or R^(c).

In another embodiment of the compound of formula (I), (II), (III), or(IV), or a pharmaceutically acceptable salt thereof, L¹ is acarbon-linked-saturated or partially-saturated 5- to 6-memberedmonocyclic ring, wherein each said ring contains 0, 1, or 2 N atoms and0 or 1 O atoms, and wherein each said L¹ is substituted by 0, 1 or 2 R⁹groups which are F, Cl, Br, C₁₋₆alk, —OR^(a), CN, —C(═O)R^(b),C(═O)OR^(a), —C(═O)NR^(a)R^(a), —SR^(a), —S(═O)R^(b), —S(═O)₂R^(b),—NR^(a)R^(a), —N(R^(a))C(═O)R^(b), —N(R^(a))C(═O)OR^(b), —C₁₋₆alkOR^(a),—C₁₋₆alkN(R^(a))C(═O)R^(b), —C₁₋₆alkOC(═O)R^(b),—C₁₋₆alkC(═O)NR^(a)R^(a), —C₁₋₆alkC(═O)OR^(a), oxo, or R^(c).

In another embodiment of the compound of formula (I), (II), (III), or(IV), or a pharmaceutically acceptable salt thereof, L¹ is acarbon-linked-unsaturated 5- to 6-membered monocyclic ring, wherein eachsaid ring contains 0, 1, or 2 N atoms and 0 or 1 O atoms, and whereineach said L¹ is substituted by 0, 1 or 2 R⁹ groups which are F, Cl, Br,C₁₋₆alk, —OR^(a), CN, —C(═O)R^(b), C(═O)OR^(a), —C(═O)NR^(a)R^(a),—SR^(a), —S(═O)R^(b), —S(═O)₂R^(b), —NR^(a)R^(a), —N(R^(a))C(═O)R^(b),—N(R^(a))C(═O)OR^(b), —C₁₋₆alkOR^(a), —C₁₋₆alkN(R^(a))C(═O)R^(b),—C₁₋₆alkOC(═O)R^(b), —C₁₋₆alkC(═O)NR^(a)R^(a), —C₁₋₆alkC(═O)OR^(a), oxo,or R^(c).

In another embodiment of the compound of formula (I), (II), (III), or(IV), or a pharmaceutically acceptable salt thereof, L¹ is acarbon-linked-saturated, partially-saturated or unsaturated 6-, 7-, 8-,9-, or 10-membered bicyclic ring, wherein each said ring contains 0, 1,or 2 N atoms and 0 or 1 O atoms, and wherein each said L¹ is substitutedby 0, 1 or 2 R⁹ groups which are F, Cl, Br, C₁₋₆alk, —OR^(a), CN,—C(═O)R^(b), C(═O)OR^(a), —C(═O)NR^(a)R^(a), —SR^(a), —S(═O)R^(b),—S(═O)₂R^(b), —NR^(a)R^(a), —N(R^(a))C(═O)R^(b), —N(R^(a))C(═O)OR^(b),—C₁₋₆alkOR^(a), —C₁₋₆alkN(R^(a))C(═O)R^(b), —C₁₋₆alkOC(═O)R^(b),—C₁₋₆alkC(═O)NR^(a)R^(a), —C₁₋₆alkC(═O)OR^(a), oxo, or R^(c).

In another embodiment of the compound of formula (I), (II), (III), or(IV), or a pharmaceutically acceptable salt thereof, L¹ is anitrogen-linked saturated, partially-saturated or unsaturated 4-, 5-,6-, or 7-membered monocyclic ring, wherein said ring contains 0, 1, 2,3, or 4 N atoms and 0 or 1 O atoms, and wherein each said L¹ issubstituted by 0, 1 or 2 R⁹ groups which are F, Cl, Br, C₁₋₆alk,—OR^(a), CN, —C(═O)R^(b), C(═O)OR^(a), —C(═O)NR^(a)R^(a), —SR^(a),—S(═O)R^(b), —S(═O)₂R^(b), —NR^(a)R^(a), —N(R^(a))C(═O)R^(b),—N(R^(a))C(═O)OR^(b), —C₁₋₆alkOR^(a), —C₁₋₆alkN(R^(a))C(═O)R^(b),—C₁₋₆alkOC(═O)R^(b), —C₁₋₆alkC(═O)NR^(a)R^(a), —C₁₋₆alkC(═O)OR^(a), oxo,or R^(c).

In another embodiment of the compound of formula (I), (II), (III), or(IV), or a pharmaceutically acceptable salt thereof, L¹ is anitrogen-linked saturated, partially-saturated or unsaturated 6-, 7-,8-, 9-, 10-, 11-, or 12-membered bicyclic ring, wherein each said ringcontains 0, 1, or 2 N atoms and 0 or 1 O atoms, and wherein each said L¹is substituted by 0, 1 or 2 R⁹ groups which are F, Cl, Br, C₁₋₆alk,—OR^(a), CN, —C(═O)R^(b), C(═O)OR^(a), —C(═O)NR^(a)R^(a), —SR^(a),—S(═O)R^(b), —S(═O)₂R^(b), —NR^(a)R^(a), —N(R^(a))C(═O)R^(b),—N(R^(a))C(═O)OR^(b), —C₁₋₆alkOR^(a), —C₁₋₆alkN(R^(a))C(═O)R^(b),—C₁₋₆alkOC(═O)R^(b), —C₁₋₆alkC(═O)NR^(a)R^(a), —C₁₋₆alkC(═O)OR^(a), oxo,or R^(c).

In another embodiment of the compound of formula (I), (II), (III), or(IV), or a pharmaceutically acceptable salt thereof, L¹ is−3-azabicyclo[3.1.0]hexanyl, azetidinyl, indolyl, phenyl, 2-pyridyl,3-pyridyl, 4-pyridyl, pyrazolyl, piperazinonyl, piperidinyl,pyrrolidinyl, dihydropyranyl, tetrahydropyridinyl,octahydropyrrolo[3,4-c]pyrrolyl, tetrahydroisoquinolinyl, which aresubstituted by 0, 1 or 2 R⁹ groups which are F, Cl, Br, C₁₋₆alk,—OR^(a), CN, —C(═O)R^(b), C(═O)OR^(a), —C(═O)NR^(a)R^(a), —SR^(a),—S(═O)R^(b), —S(═O)₂R^(b), —NR^(a)R^(a), —N(R^(a))C(═O)R^(b),—N(R^(a))C(═O)OR^(b), —C₁₋₆alkOR^(a), —C₁₋₆alkN(R^(a))C(═O)R^(b),—C₁₋₆alkOC(═O)R^(b), —C₁₋₆alkC(═O)NR^(a)R^(a), —C₁₋₆alkC(═O)OR^(a), oxo,or R^(c).

In another embodiment of the compound of formula (I), (II), (III), or(IV), or a pharmaceutically acceptable salt thereof, R¹ is selected fromthe group consisting of: Cl; Br; —C≡C—CH₃; —NH—CH(CH₃)₂; —NHCH₂CH₂OCH₃;—NHCH₂CH₂OH;

In another embodiment of the compound of formula (I), (II), (III), or(IV), or a pharmaceutically acceptable salt thereof. R¹ is selected fromthe group consisting of:

In another embodiment of the compound of formula (I), (II), (III), or(IV), or a pharmaceutically acceptable salt thereof, R¹ is selected fromthe group consisting of:

In another embodiment of the compound of formula (I), (II), (III), or(IV), or a pharmaceutically acceptable salt thereof, each R² and R³ isindependently H, F, Cl, Br, CN, OH, OC₁₋₄alk, C₁₋₄alk or C₁₋₄haloalk.

In another embodiment of the compound of formula (I), (II), (III), or(IV), or a pharmaceutically acceptable salt thereof, R⁶ is H, F, orC₁₋₄alk.

In another embodiment of the compound of formula (I), (II), (III), or(IV), or a pharmaceutically acceptable salt thereof, R^(4a) is H, F, OH,or methyl.

In another embodiment of the compound of formula (I), (II), (III), or(IV), or a pharmaceutically acceptable salt thereof, R^(4b) is oxo and mis 1

In another embodiment of the compound of formula (I), (II), (III), or(IV), or a pharmaceutically acceptable salt thereof, R^(4a) is H and mis 0.

In another embodiment of the compound of formula (I), (II), (III), or(IV), or a pharmaceutically acceptable salt thereof, R⁵ is pyridinyl.

In another embodiment of the compound of formula (I), (II), (III), or(IV), or a pharmaceutically acceptable salt thereof, R⁵ is unsaturated9- to 10-membered bicyclo-heterocyclic ring.

In another embodiment of the compound of formula (I), (II), (III), or(IV), or a pharmaceutically acceptable salt thereof, R⁵ is 11- to15-membered tricyclo-heterocyclic ring.

In another embodiment of the compound of formula (I), (II), (III), or(IV), or a pharmaceutically acceptable salt thereof, the group —Y—R⁵ is:

wherein each R⁵ is substituted by 1 or 2 R⁸ groups.

In another embodiment of the compound of formula (I), (II), (III), or(IV), or a pharmaceutically acceptable salt thereof, the group —Y—R⁵ is:

wherein each R⁵ is substituted by 1 or 2 R⁸ groups.

In another embodiment of the compound of formula (I), (II), (III), or(IV), or a pharmaceutically acceptable salt thereof, the group —Y—R⁵ is:

In another embodiment of the compound of formula (I), (II), (III), or(IV), or a pharmaceutically acceptable salt thereof, Y is a bond or—C(═O).

In another embodiment of the compound of formula (I), (II), (III), or(IV), or a pharmaceutically acceptable salt thereof, Y is a bond.

In another embodiment of the compound of formula (I), (II), (III), or(IV), or a pharmaceutically acceptable salt thereof, R⁸ is independentlyF, Br, Cl, CF₃, methyl, methoxy, or CN.

In another embodiment of the compound of formula (I), (II), (III), or(IV), or a pharmaceutically acceptable salt thereof, R^(a) is H orC₁₋₆alk substituted by 0 or 1 —OH, —OC₁₋₄alk, —OC(═O)C₁₋₄alk, or—N(C₁₋₄alk)C₁₋₄alk.

In another embodiment of the compound of formula (I), (II), (III), or(IV), or a pharmaceutically acceptable salt thereof, R^(c) is aC₀₋₄alk-carbon-linked saturated, partially-saturated or unsaturated 3-,4- 5-, or 6-membered monocyclic ring containing 0, 1, or 2 N atoms and 0or 1 atom which are O or S, which is substituted by 0 or 1 R¹¹ groupswhich are F, C₁₋₆alk, C₁₋₄haloalk, or —OR^(a).

In another embodiment of the compound of formula (I), (II), (III), or(IV), or a pharmaceutically acceptable salt thereof, R^(c) is pyridyl,phenyl, or 1,2,4-oxadiazolyl.

Another aspect of the current invention relates to compounds having thegeneral structure of formula (ID:

or a pharmaceutically acceptable salt thereof, wherein:

Ring D is -L¹;

X¹ is N or CR⁶;

X² is N or CR²;

X³ is N or CR³;

X⁴ is N or CR⁶;

wherein 1 to 2 of X¹, X², X³, and X⁴ are N;

Y is a C₀₋₄alk, —C(═O), SO, or SO₂;

each R² and R³ is independently H, halo, CN, OH, —OC₁₋₄alk, C₁₋₄alk,C₁₋₄haloalk, —C(═O)C₁₋₄alk, —C(═O)NR^(a)R^(a), —C₀₋₄alkNH—C(═O)R^(a), orR^(c);

or alternatively the ring containing X¹, X², X³, X⁴ and X⁵ can be fusedto ring A, ring B, or ring C; having the formula:

wherein each said ring A, ring B, or ring C is a fused 4- to6-membered-saturated, -partially saturated, or -unsaturated-carbocyclicor -heterocyclic ring containing 0, 1, 2, or 3 heteroatoms; and issubstituted by 0, 1, or 2 R¹⁰ groups;

R^(4a) is H, OH, halo, C₁₋₄alk, or C₁₋₄haloalk;

R^(4b) is halo, CN, OH, OC₁₋₄alk, C₁₋₄alk, C₁₋₄haloalk, or oxo;

R⁵ is pyridinyl or unsaturated 9- to 10-membered bicyclo-heterocyclicring; wherein each R⁵ is substituted by 0, 1, 2 or 3 R⁸ groups;

R⁶ is independently H, halo, CN, OH, OC₁₋₄alk, C₁₋₄alk or C₁₋₄haloalk;

m is 0, 1, 2, 3, or 4;

each of p and q is independently 0, 1, 2, 3, 4, 5, or 6; wherein the sumof p and q is 2 to 6;

the ring containing p and q contains 0, 1, or 2 double bonds;

R^(a) is independently H or R^(b);

R^(b) is independently phenyl, benzyl, or C₁₋₆alk, wherein said phenyl,benzyl, or C₁₋₆alk substituted by 0, 1, 2 or 3 substituents which are,independently, halo, C₁₋₄alk, C₁₋₃haloalk, —OH, —OC₁₋₄alk, —NH₂,—NHC₁₋₄alk, —OC(═O)C₁₋₄alk, or —N(C₁₋₄alk)C₁₋₄alk;

R^(c) is C₀₋₄alk-L²;

each L¹ is independently a carbon-linked or nitrogen-linked saturated,partially-saturated or unsaturated 3-, 4-, 5-, 6-, or 7-memberedmonocyclic ring or a saturated, partially-saturated or unsaturated 6-,7-, 8-, 9-, 10-, 11-, or 12-membered bicyclic ring, wherein each saidring contains 0, 1, 2, 3, or 4 N atoms and 0, 1, or 2 atoms which are Oor S; wherein each L¹ is independently substituted by 0, 1, 2 or 3 R⁹groups;

each L² is independently a carbon-linked or nitrogen-linked saturated,partially-saturated or unsaturated 3-, 4-, 5-, 6-, or 7-memberedmonocyclic ring or a saturated, partially-saturated or unsaturated 6-,7-, 8-, 9-, 10-, 11-, or 12-membered bicyclic ring, wherein each saidring contains 0, 1, 2, 3, or 4 N atoms and 0, 1, or 2 atoms which are Oor S; wherein each L² is independently substituted by 0, 1, 2 or 3 R¹¹groups;

R⁸ is halo, CN, OH, OC₁₋₄alk, C₁₋₄alk, C₁₋₄haloalk, OC₁₋₄haloalk,—C(═O)R^(b), —C(═O)R^(c), —C(═O)NHR^(b), —C(═O)NHR^(c), —S(═O)₂R^(b),—S(═O)₂R^(c), —S(═O)₂NR^(a)R^(a), R^(b), R^(c), NO₂, OR^(b), or OR^(c);

R⁹ is F, Cl, Br, C₁₋₆alk, C₁₋₄haloalk, —OR^(a), —OC₁₋₄haloalk, CN,—C(═O)R^(b), —C(═O)OR^(a), —C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a),—OC(═O)R^(b), —OC(═O)NR^(a)R^(a), —OC₁₋₆alkNR^(a)R^(a), —OC₁₋₆alkOR^(a),—SR^(a), —S(═O)R^(b), —S(═O)₂R^(b), —S(═O)₂NR^(a)R^(a), —NR^(a)R^(a),—N(R^(a))C(═O)R^(b), —N(R^(a))C(═O)OR^(b), —N(R^(a))C(═O)NR^(a)R^(a),—N(R^(a))C(═NR^(a))NR^(a)R^(a), —N(R^(a))S(═O)₂R^(b),—N(R^(a))S(═O)₂NR^(a)R^(a), —NR^(a)C₁₋₆alkNR^(a)R^(a),—NR^(a)C₁₋₆alkOR^(a), —C₁₋₆alkNR^(a)R^(a), —C₁₋₆alkOR^(a),—C₁₋₆alkN(R^(a))C(═O)R^(b), —C₁₋₆alkOC(═O)R^(b),—C₁₋₆alkC(═O)NR^(a)R^(a), —C₁₋₆alkC(═O)OR^(a), oxo, or R^(c);

R¹⁰ is oxo, C₁₋₆alk, C₁₋₃haloalk, —OH, —OC₁₋₄alk, —NH₂, —NHC₁₋₄alk,—OC(═O)C₁₋₄alk, or —N(C₁₋₄alk)C₁₋₄alk; and

R¹¹ is F, Cl, Br, C₁₋₆alk, C₁₋₄haloalk, —OR^(a), —OC₁₋₄haloalk, CN,—C(═O)R^(b), —C(═O)OR^(a), —C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a),—OC(═O)R^(b), —OC(═O)NR^(a)R^(a), —OC₁₋₆alkNR^(a)R^(a), —OC₁₋₆alkOR^(a),—SR^(a), —S(═O)R^(b), —S(═O)₂R^(b), —S(═O)₂NR^(a)R^(a), —NR^(a)R^(a),—N(R^(a))C(═O)R^(b), —N(R^(a))C(═O)OR^(b), —N(R^(a))C(═O)NR^(a)R^(a),—N(R^(a))C(═NR^(a))NR^(a)R^(a), —N(R^(a))S(═O)₂R^(b),—N(R^(a))S(═O)₂NR^(a)R^(a), —NR^(a)C₁₋₆alkNR^(a)R^(a),—NR^(a)C₁₋₆alkOR^(a), —C₁₋₆alkNR^(a)R^(a), —C₁₋₆alkOR^(a),—C₁₋₆alkN(R^(a))C(═O)R^(b), —C₁₋₆alkOC(═O)R^(b),—C₁₋₆alkC(═O)NR^(a)R^(a), —C₁₋₆alkC(═O)OR^(a), or oxo.

In another embodiment of the compound of formula (I), (II), (III), or(IV), or a pharmaceutically acceptable salt thereof, the group

is azetidinyl, pyrrolidinyl, piperidinyl, or azepanyl.

In another embodiment of the compound of formula (I), (II), (III), or(IV), or a pharmaceutically acceptable salt thereof, the compound offormula (II) has the formula:

In another embodiment of the compound of formula (I), (II), (III), or(IV), or a pharmaceutically acceptable salt thereof, the compound offormula (II) has the formula:

In another embodiment of the compound of formula (I), (II), (III), or(IV), or a pharmaceutically acceptable salt thereof, the compound offormula (II) has the formula:

In another embodiment of the compound of formula (IIg), R^(4b) is oxo; mis 1; and R⁵ is unsaturated 10-membered bicyclo-heterocyclic ring;wherein each R⁵ ring is substituted by 0, 1, or 2 R⁸ groups.

In another embodiment of the compound of formula (IIg), said compoundhas the formula

wherein m is 0; and R⁵ is unsaturated 10-membered bicyclo-heterocyclicring; wherein each R⁵ ring is substituted by 0, 1, or 2 R⁸ groups.

In another embodiment of any of the compound of the formula (IIa),(IIb), (IIc), (IId), (IIe), (IIf), and (IIg), the group —Y—R⁵ is:

Y is a bond; wherein each R⁵ is substituted by 1 or 2 R⁸ groups; and R⁸is independently F, Cl, Br, methyl, ethyl, isopropyl, methoxy, CN, CF₃,OH, or OCF₃.

In another embodiment of any of the compound of the formula (IIa),(IIb), (IIc), (IId), (IIe), (IIf), and (IIg), or a pharmaceuticallyacceptable salt thereof, the group —Y—R⁵ is:

Y is a bond; wherein R⁸ is independently F, Cl, Br, methyl, ethyl,isopropyl, methoxy, CN, CF₃, OH, or OCF₃.

Another aspect of the current invention relates to compounds having thegeneral structure of formula (III):

or a pharmaceutically-acceptable salt thereof, wherein:

X¹ is N or CR⁶;

R¹ is F, Cl, Br, I, C₁₋₈alk, C₁₋₄haloalk, —OR^(a), —OR^(c),—N(R^(a))C(═O)R^(b), —C(═O)R^(a), —C(═O)R^(c), —C(═O)—O—R^(a),—NR^(a)R^(c), —N(R^(c))C(═O)R^(b), —N(R^(a))C(═O)R^(c),—C(═O)NR^(a)R^(b), —C(═O)NR^(a)R^(c) or C₀₋₄alk-L¹; wherein said C₁₋₈alkgroup is substituted by 0, 1, 2 or 3 groups selected from halo,C₁₋₃haloalk, —OH, —OC₁₋₄alk, —NH₂, —NHC₁₋₄alk,

—OC(═O)C₁₋₄alk, or —N(C₁₋₄alk)C₁₋₄alk;

Y is a C₀₋₄alk, —C(═O), SO, or SO₂;

each of R², R³, R^(4b), R⁶ and R⁸ is independently H, F, Cl, Br, I, CN,OH, OC₁₋₄alk, C₁₋₄alk or C₁₋₄haloalk;

or alternatively R² and R³ can form an optionally substituted 5- to6-membered-saturated, -partially saturated, or -unsaturated-heterocyclicring fused to the ring containing X¹;

R^(4a) is H, C₁₋₄alk, or C₁₋₄haloalk;

R⁵ is pyridinyl or unsaturated 9- or 10-membered bicyclo-heterocyclicring;

wherein each R⁵ is substituted by 0, 1, 2 or 3 R⁸ groups; and is notsubstituted by oxo;

m is 1, 2, 3, or 4;

each of p and q is independently 0, 1, 2, 3, 4, 5, or 6; wherein the sumof p and q is 2 to 6;

R^(a) is independently H or R^(b);

R^(b) is independently phenyl, benzyl, or C₁₋₆alk, wherein said phenyl,benzyl, and C₁₋₆alk are being substituted by 0, 1, 2 or 3 substituentsselected from halo, C₁₋₄alk, C₁₋₃haloalk, —OH, —OC₁₋₄alk, —NH₂,—NHC₁₋₄alk, —OC(═O)C₁₋₄alk, or —N(C₁₋₄alk)C₁₋₄alk;

R^(c) is C₀₋₄alk-L²; and

each of L¹ and L² is independently a carbon-linked or nitrogen-linkedsaturated, partially-saturated or unsaturated 3-, 4-, 5-, 6-, or7-membered monocyclic ring or a saturated, partially-saturated orunsaturated 8-, 9-, 10-, 11-, or 12-membered bicyclic ring, wherein eachsaid ring contains 0, 1, 2, 3, or 4 N atoms and 0, 1, or 2 atomsselected from O and S; wherein each L¹and L² is independentlysubstituted by 0, 1, 2 or 3 R⁹ groups selected from F, Cl, Br, C₁₋₆alk,C₁₋₄haloalk, —OR^(a), —OC₁₋₄haloalk, CN, —C(═O)R^(b), —C(═O)OR^(a),—C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a), —OC(═O)R^(b),—OC(═O)NR^(a)R^(a), —OC₂₋₆alkNR^(a)R^(a), —OC₂₋₆alkOR^(a), —SR^(a),—S(═O)R^(b), —S(═O)₂R^(b), —S(═O)₂NR^(a)R^(a), —NR^(a)R^(a),—N(R^(a))C(═O)R^(b), —N(R^(a))C(═O)OR^(b), —N(R^(a))C(═O)NR^(a)R^(a),—N(R^(a))C(═NR^(a))NR^(a)R^(a), —N(R^(a))S(═O)₂R^(b),—N(R^(a))S(═O)₂NR^(a)R^(a), —NR^(a)C₂₋₆alkNR^(a)R^(a),—NR^(a)C₂₋₆alkOR^(a), —C₁₋₆alkNR^(a)R^(a), —C₁₋₆alkOR^(a),—C₁₋₆alkN(R^(a))C(═O)R^(b), —C₁₋₆alkOC(═O)R^(b),—C₁₋₆alkC(═O)NR^(a)R^(a), —C₁₋₆alkC(═O)OR^(a) or oxo;

with the proviso that: when all X¹, X², and X³ are CR³; each of p and qis 2; and R³ is methyl; then R¹ is F, Cl, Br, I, C₁₋₈alk, C₁₋₄haloalk,—OR^(a), —OR^(c), —N(R^(a))C(═O)R^(b), —NR^(a)R^(c),—N(R^(c))C(═O)R^(b), —N(R^(a))C(═O)R^(c) or C₀₋₄alk-L¹; wherein saidC₁₋₈alk group is substituted by 0, 1, 2 or 3 groups selected from halo,C₁₋₃haloalk, —OH, —OC₁₋₄alk, —NH₂, —NHC₁₋₄alk, —OC(═O)C₁₋₄alk, or—N(C₁₋₄alk)C₁₋₄alk.

In another embodiment of the compound of formula (I), (II), (III), or(IV), or a pharmaceutically acceptable salt thereof, R⁵ is notsubstituted by oxo.

In another embodiment of the compound of formula (I), (II), (III), or(IV), or a pharmaceutically acceptable salt thereof, the group:

wherein each of Y₁, Y₂, Y₃, M₁, M₂, M₃, and M₄ is independently CR¹⁰ ora heteroatom selected from S, O, or NR¹¹; wherein no more than of Y₁,Y₂, Y₃, M₁, M₂, M₃, and M₄ are N; and

wherein R¹⁰ is H, halo, C₁₋₄alk, C₁₋₃haloalk, —OH, —OC₁₋₄alk, —NH₂,—NHC₁₋₄alk, —OC(═O)C₁₋₄alk, or —N(C₁₋₄alk)C₁₋₄alk; and R^(H) is H,C₁₋₄alk, or C₁₋₃haloalk.

In another embodiment of the compound of formula (I), (II), (III), or(IV), or a pharmaceutically acceptable salt thereof, the group

In another embodiment of the compound of formula (I), (II), (III), or(IV), or a pharmaceutically acceptable salt thereof, the group

each of p and q is 2; R⁵ is unsaturated 9-membered bicyclo-heterocyclicring; and Y is C₀₋₄alk; and R¹ is C₀₋₄alk-L¹.

In another embodiment of the compound of formula (I), (II), (III), or(IV), or a pharmaceutically acceptable salt thereof, the group

In another embodiment of the compound of formula (I), (II), (III), or(IV), or a pharmaceutically acceptable salt thereof, m is 1 or 2.

In another embodiment of the compound of formula (I), (II), (III), or(IV), or a pharmaceutically acceptable salt thereof, p is 0, 1, or 2.

In another embodiment of the compound of formula (I), (II), (III), or(IV), or a pharmaceutically acceptable salt thereof, q is 0, 1, or 2.

In another embodiment of the compound of formula (I), (II), (III), or(IV), or a pharmaceutically acceptable salt thereof, R¹ is F, Cl, Br, I,—OR^(a), —C(═O)—O—R^(a), —C(═O)NR^(a)R^(b), —OR^(c), or—C(═O)NR^(a)R^(c).

In another embodiment of the compound of formula (I), (II), (III), or(IV), or a pharmaceutically acceptable salt thereof, R¹ is a saturated,partially-saturated or unsaturated 4-, 5-, 6-, or 7-membered monocyclicring, wherein each said ring contains 0, 1, 2, or 3 N atoms and 0, 1, or2 O atoms, and wherein each said ring is substituted by 0, 1, 2 or 3 R⁹groups selected from F, Cl, Br, C₁₋₆alk, C₁₋₄haloalk, —OR^(a),—OC₁₋₄haloalk, CN, —C(═O)R^(b), —C(═O)OR^(a), —NR^(a)R^(a), SR^(a), oroxo.

In another embodiment of the compound of formula (I), (II), (III), or(IV), or a pharmaceutically acceptable salt thereof, R¹ is a saturatedor partially-saturated 5- to 6-membered monocyclic ring, wherein eachsaid ring contains 0, 1, 2, or 3 N atoms and 0, 1, or 2 0 atoms, andwherein each said ring is substituted by 0, 1, 2 or 3 R⁹ groups selectedfrom F, Cl, Br, C₁₋₆alk, C₁₋₄haloalk, —OR^(a), —OC₁₋₄haloalk, CN,—C(═O)R^(b), —C(═O)OR^(a), —NR^(a)R^(a), SR^(a), or oxo.

In another embodiment of the compound of formula (I), (II), (III), or(IV), or a pharmaceutically acceptable salt thereof, R¹ is a saturated,partially-saturated or unsaturated 8-, 9-, 10-, 11-, or 12-memberedbicyclic ring, wherein each said ring contains 0, 1, 2, or 3 N atoms and0, 1, or 2 O atoms, and wherein each said ring is substituted by 0, 1, 2or 3 R⁹ groups selected from F, Cl, Br, C₁₋₆alk, C₁₋₄haloalk, —OR^(a),—OC₁₋₄haloalk, CN, —C(═O)R^(b), —C(═O)OR^(a), —NR^(a)R^(a), SR^(a), oroxo.

In another embodiment of the compound of formula (I), (II), (III), or(IV), or a pharmaceutically acceptable salt thereof, R¹ is anitrogen-linked saturated, partially-saturated or unsaturated 4-, 5-,6-, or 7-membered monocyclic ring wherein each said ring contains 0, 1,2, 3, or 4 N atoms and 0, 1, or 2 atoms selected from O and S;substituted by 0, 1, 2 or 3 R⁹ groups selected from F, Cl, Br, C₁₋₆alk,C₁₋₄haloalk, —OR^(a), —OC₁₋₄haloalk, CN, —C(═O)R^(b), —C(═O)OR^(a),—NR^(a)R^(a), SR^(a), or oxo.

In another embodiment of the compound of formula (I), (II), (III), or(IV), or a pharmaceutically acceptable salt thereof, R¹ is cyclohexyl,cyclopentyl, cyclopentenyl, cyclohexenyl, cycloheptyl, azetidinyl,phenyl, 2-pyridyl, 3-pyridyl, pyrazolyl, morpholinyl, pyrimidyl,piperazinyl, piperidinyl, dihydropyranyl, tetrahydropyranyl,tetrahydrofuranyl, tetrahydropyridinyl, tetrahydrothiopyranyl,oxaspiro[3.5]nonyl, azepanyl, oxepanyl, or quinolinyl, all of which aresubstituted by 0, 1, 2 or 3 R⁹ groups selected from F, Cl, Br, C₁₋₆alk,C₁₋₄haloalk, —OR^(a), CN, —C(═O)R^(b), —C(═O)OR^(a), —SR^(a), or oxo.

In another embodiment of the compound of formula (I), (II), (III), or(IV), or a pharmaceutically acceptable salt thereof, R¹ is:

wherein the dotted bond is an optional double bond.

In another embodiment of the compound of formula (I), (II), (III), or(IV), or a pharmaceutically acceptable salt thereof, each R² and R³ isindependently H, F, Cl, Br, CN, OH, OC₁₋₄alk, C₁₋₄alk or C₁₋₄haloalk.

In another embodiment of the compound of formula (I), (II), (III), or(IV), or a pharmaceutically acceptable salt thereof, each R² and R³ isH, C₁₋₄alk, or C₁₋₄haloalk.

In another embodiment of the compound of formula (I), (II), (III), or(IV), or a pharmaceutically acceptable salt thereof, R² and R³ are H.

In another embodiment of the compound of formula (I), (II), (III), or(IV), or a pharmaceutically acceptable salt thereof, R² and R³ form anoptionally substituted 5- to 6-membered-saturated, -partially saturated,or -unsaturated-heterocyclic ring fused to the ring containing X¹.

In another embodiment of the compound of formula (I), (II), (III), or(IV), or a pharmaceutically acceptable salt thereof, X¹ is N.

In another embodiment of the compound of formula (I), (II), (III), or(IV), or a pharmaceutically acceptable salt thereof, X¹ is CR⁶; whereinR⁶ is H, F, Cl, Br, I, OC₁₋₄alk, or C₁₋₄alk.

In another embodiment of the compound of formula (I), (II), (III), or(IV), or a pharmaceutically acceptable salt thereof, R⁶ is H or C₁₋₄alk.

In another embodiment of the compound of formula (I), (II), (III), or(IV), or a pharmaceutically acceptable salt thereof, R^(4a) is H orC₁₋₄alk.

In another embodiment of the compound of formula (I), (II), (III), or(IV), or a pharmaceutically acceptable salt thereof, R^(4b) isindependently H, F, CN, OC₁₋₄alk, C₁₋₄alk or C₁₋₄haloalk.

In another embodiment of the compound of formula (I), (II), (III), or(IV), or a pharmaceutically acceptable salt thereof, each of R^(4a) andR^(4b) is H.

In another embodiment of the compound of formula (I), (II), (III), or(IV), or a pharmaceutically acceptable salt thereof, R⁵ is pyridinyl.

In another embodiment of the compound of formula (I), (II), (III), or(IV), or a pharmaceutically acceptable salt thereof, R⁵ is unsaturated9- or 10-membered bicyclo-heterocyclic ring; wherein the ring isaromatic.

In another embodiment of the compound of formula (I), (II), (III), or(IV), or a pharmaceutically acceptable salt thereof, R⁵ is unsaturated9-membered bicyclo-heterocyclic ring; wherein the ring is aromatic.

In another embodiment of the compound of formula (I), (II), (III), or(IV), or a pharmaceutically acceptable salt thereof, R⁵ is unsaturated10-membered bicyclo-heterocyclic ring; wherein the ring is aromatic.

In another embodiment of the compound of formula (I), (II), (III), or(IV), or a pharmaceutically acceptable salt thereof, the group —Y—R⁵ is:

In another embodiment of the compound of formula (I), (II), (III), or(IV), or a pharmaceutically acceptable salt thereof, the group —Y—R⁵ is:

and Y is C(═O).

In another embodiment of the compound of formula (I), (II), (III), or(IV), or a pharmaceutically acceptable salt thereof, Y is —C(═O).

In another embodiment of the compound of formula (I), (II), (III), or(IV), or a pharmaceutically acceptable salt thereof, Y is a bond orC₁₋₃alk.

In another embodiment of the compound of formula (I), (II), (III), or(IV), or a pharmaceutically acceptable salt thereof, R⁵ is:

In another embodiment of the compound of formula (I), (II), (III), or(IV), or a pharmaceutically acceptable salt thereof, R⁸ is independentlyH, F, CN, OC₁₋₄alk, C₁₋₄alk or C₁₋₄haloalk.

In another embodiment of the compound of formula (I), (II), (III), or(IV), or a pharmaceutically acceptable salt thereof, R⁸ is H.

In another embodiment of the compound of formula (I), (II), (III), or(IV), or a pharmaceutically acceptable salt thereof, R^(a) is H orC₁₋₆alk substituted by 0 or 1 —OH, —OC₁₋₄alk, —OC(═O)C₁₋₄alk, or—N(C₁₋₄alk)C₁₋₄alk.

In another embodiment of the compound of formula (I), (II), (III), or(IV), or a pharmaceutically acceptable salt thereof, R^(c) is acarbon-linked saturated, partially-saturated or unsaturated 3-, 4- 5-,or 6-membered monocyclic ring containing 0 or 1 N atom and 0 or 1 atomselected from O and S, which is substituted by 0 or 1 R⁹ groups selectedfrom F, C₁₋₆alk, C₁₋₄haloalk, or —OR^(a).

In another embodiment of the compound of formula (I), (II), (III), or(IV), or a pharmaceutically acceptable salt thereof, R^(c) is anitrogen-linked saturated, partially-saturated, or unsaturated 4-, 5-,6- or 7-membered ring heterocycle containing the linking nitrogen and 0,1 or 2 additional nitrogen atoms and containing 0 or 1 sulfur or oxygenatom, the heterocycle being substituted by 0, 1, 2 or 3 R⁹ groupsselected from F, Cl, Br, C₁₋₄alk, C₁₋₄haloalk, —OC₁₋₄alk, —NH₂,—NHC₁₋₄alk, —N(C₁₋₄alk)C₁₋₄alk, or oxo.

In another embodiment of the compound of formula (I), (II), (III), or(IV), or a pharmaceutically acceptable salt thereof, R^(c) is aC₀₋₄alk-saturated, partially-saturated or unsaturated 3-, 5-, or6-membered monocyclic ring containing 0 or 1 N atom and 0 or 1 atomselected from O and S, which is substituted by 0 or 1 R⁹ groups selectedfrom F, C₁₋₆alk, C₁₋₄haloalk, or —OR^(a).

In another embodiment of the compound of formula (I), (II), (III), or(IV), or a pharmaceutically acceptable salt thereof, the compound hasthe following formula (Ma):

wherein R¹ is F, Cl, Br, I, C₁₋₈alk, C₁₋₄haloalk, —OR^(a), —OR^(c),—N(R^(a))C(═O)R^(b), —NR^(a)R^(c), —N(R^(c))C(═O)R^(b),—N(R^(a))C(═O)R^(c) or C₀₋₄alk-L¹; wherein said C₁₋₈alk group issubstituted by 0, 1, 2 or 3 groups selected from halo, C₁₋₃haloalk, —OH,—OC₁₋₄alk, —NH₂, —NHC₁₋₄alk, —OC(═O)C₁₋₄alk, or —N(C₁₋₄alk)C₁₋₄alk; andR³ is not methyl.

Another aspect of the current invention relates to compounds having thegeneral structure of formula (IV):

or any pharmaceutically-acceptable salt thereof, wherein:

Ring D is -L¹;

X¹ is N or CR⁶;

Y is a C₀₋₄alk, —C(═O), SO, or SO₂;

each of R², R³, R^(4b), R⁶ and R⁸ is independently H, F, Cl, Br, I, CN,OH, OC₁₋₄alk, C₁₋₄alk or C₁₋₄haloalk;

or alternatively R² and R³ can form an optionally substituted 5- to6-membered-saturated, -partially saturated, or -unsaturated-heterocyclicring fused to the ring containing X¹;

R^(4a) is H, C₁₋₄alk, or C₁₋₄haloalk;

R⁵ is pyridinyl or unsaturated 9- or 10-membered bicyclo-heterocyclicring; wherein each R⁵ is substituted by 0, 1, 2 or 3 R⁸ groups; and isnot substituted by oxo;

m is 1, 2, 3, or 4;

each of p and q is independently 0, 1, 2, 3, 4, 5, or 6; wherein the sumof p and q is 2 to 6;

R^(a) is independently H or R^(b);

R^(b) is independently phenyl, benzyl, or C₁₋₆alk, wherein said phenyl,benzyl, and C₁₋₆alk are being substituted by 0, 1, 2 or 3 substituentsselected from halo, C₁₋₄alk, C₁₋₃haloalk, —OH, —OC₁₋₄alk, —NH₂,—NHC₁₋₄alk, —OC(═O)C₁₋₄alk, and —N(C₁₋₄alk)C₁₋₄alk; and

each of L¹and L² is independently a carbon-linked or nitrogen-linkedsaturated, partially-saturated or unsaturated 3-, 4-, 5-, 6-, or7-membered monocyclic ring or a saturated, partially-saturated orunsaturated 8-, 9-, 10-, 11-, or 12-membered bicyclic ring, wherein eachsaid ring contains 0, 1, 2, 3, or 4 N atoms and 0, 1, or 2 atomsselected from O and S; wherein each L¹and L² is independentlysubstituted by 0, 1, 2 or 3 R⁹ groups selected from F, Cl, Br, C₁₋₆alk,C₁₋₄haloalk, —OR^(a), —OC₁₋₄haloalk, CN, —C(═O)R^(b), —C(═O)OR^(a),—C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a), —OC(═O)R^(b),—OC(═O)NR^(a)R^(a), —OC₂₋₆alkNR^(a)R^(a), —OC₂₋₆alkOR^(a), —SR^(a),—S(═O)R^(b), —S(═O)₂R^(b), —S(═O)₂NR^(a)R^(a), —NR^(a)R^(a),—N(R^(a))C(═O)R^(b), —N(R^(a))C(═O)OR^(b), —N(R^(a))C(═O)NR^(a)R^(a),—N(R^(a))C(═NR^(a))NR^(a)R^(a), —N(R^(a))S(═O)₂R^(b),—N(R^(a))S(═O)₂NR^(a)R^(a), —NR^(a)C₂₋₆alkNR^(a)R^(a),—NR^(a)C₂₋₆alkOR^(a), —C₁₋₆alkNR^(a)R^(a), —C₁₋₆alkOR^(a),—C₁₋₆alkN(R^(a))C(═O)R^(b), —C₁₋₆alkOC(═O)R^(b),—C₁₋₆alkC(═O)NR^(a)R^(a), —C₁₋₆alkC(═O)OR^(a) and oxo.

In another embodiment of the compound of formula (I), (II), (III), or(IV), or a pharmaceutically acceptable salt thereof, the group

is azetidinyl, pyrrolidinyl, piperidinyl, or azepanyl; wherein eachgroup is not substituted by oxo.

In another embodiment of the compound of formula (I), (II), (III), or(IV), or a pharmaceutically acceptable salt thereof, the group

is azetidinyl; which is not substituted by oxo.

In another embodiment of the compound of formula (I), (II), (III), or(IV), or a pharmaceutically acceptable salt thereof, the group

is pyrrolidinyl; which is not substituted by oxo.

In another embodiment of the compound of formula (I), (II), (III), or(IV), or a pharmaceutically acceptable salt thereof, the group

is piperidinyl; which is not substituted by oxo.

In another embodiment of the compound of formula (I), (II), (III), or(IV), or a pharmaceutically acceptable salt thereof, the group

is azepanyl; which is not substituted by oxo.

In another embodiment of the compound of formula (I), (II), (III), or(IV), or a pharmaceutically acceptable salt thereof, the group

is azetidinyl or piperidinyl; which is not substituted by oxo; and Y is—C(═O), SO, or SO₂.

In another embodiment of the compound of formula (I), (II), (III), or(IV), or a pharmaceutically acceptable salt thereof, the group

is azetidinyl; which is not substituted by oxo; and Y is —C(═O), SO, orSO₂.

In another embodiment of the compound of formula (I), (II), (III), or(IV), or a pharmaceutically acceptable salt thereof, ring D is acarbon-linked saturated, partially-saturated or unsaturated 4-, 5-, 6-,or 7-membered monocyclic ring, wherein each said ring contains 0, 1, 2,3, or 4 N atoms and 0, 1, or 2 atoms selected from O and S;independently substituted by 0, 1, 2 or 3 R⁹ groups selected from F, Cl,Br, C₁₋₆alk, C₁₋₄haloalk, —OR^(a), —OC₁₋₄haloalk, CN, —C(═O)R^(b),—C(═O)OR^(a), —C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a), —OC(═O)R^(b),—OC(═O)NR^(a)R^(a), —OC₂₋₆alkNR^(a)R^(a), —OC₂₋₆alkOR^(a), —SR^(a),—S(═O)R^(b), —S(═O)₂R^(b), —S(═O)₂NR^(a)R^(a), —NR^(a)R^(a),—N(R^(a))C(═O)R^(b), —N(R^(a))C(═O)OR^(b), —N(R^(a))C(═O)NR^(a)R^(a),—N(R^(a))C(═NR^(a))NR^(a)R^(a), —N(R^(a))S(═O)₂R^(b),—N(R^(a))S(═O)₂NR^(a)R^(a), —NR^(a)C₂₋₆alkNR^(a)R^(a),—NR^(a)C₂₋₆alkOR^(a), —C₁₋₆alkNR^(a)R^(a), —C₁₋₆alkOR^(a),—C₁₋₆alkN(R^(a))C(═O)R^(b), —C₁₋₆alkOC(═O)R^(b),—C₁₋₆alkC(═O)NR^(a)R^(a), —C₁₋₆alkC(═O)OR^(a) and oxo.

In another embodiment of the compound of formula (I), (II), (III), or(IV), or a pharmaceutically acceptable salt thereof, ring D is acarbon-linked-saturated, partially-saturated or unsaturated 8-, 9-, 10-,11-, or 12-membered bicyclic ring, wherein each said ring contains 0, 1,2, 3, or 4 N atoms and 0, 1, or 2 atoms selected from O and S;independently substituted by 0, 1, 2 or 3 R⁹ groups selected from F, Cl,Br, C₁₋₆alk, C₁₋₄haloalk, —OR^(a), —OC₁₋₄haloalk, CN, —C(═O)R^(b),—C(═O)OR^(a), —C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a), —OC(═O)R^(b),—OC(═O)NR^(a)R^(a), —OC₂₋₆alkNR^(a)R^(a), —OC₂₋₆alkOR^(a), —SR^(a),—S(═O)R^(b), —S(═O)₂R^(b), —S(═O)₂NR^(a)R^(a), —NR^(a)R^(a),—N(R^(a))C(═O)R^(b), —N(R^(a))C(═O)OR^(b), —N(R^(a))C(═O)NR^(a)R^(a),—N(R^(a))C(═NR^(a))NR^(a)R^(a), —N(R^(a))S(═O)₂R^(b),—N(R^(a))S(═O)₂NR^(a)R^(a), —NR^(a)C₂₋₆alkNR^(a)R^(a),—NR^(a)C₂₋₆alkOR^(a), —C₁₋₆alkNR^(a)R^(a), —C₁₋₆alkOR^(a),—C₁₋₆alkN(R^(a))C(═O)R^(b), —C₁₋₆alkOC(═O)R^(b),—C₁₋₆alkC(═O)NR^(a)R^(a), —C₁₋₆alkC(═O)OR^(a) and oxo.

In another embodiment of the compound of formula (I), (II), (III), or(IV), or a pharmaceutically acceptable salt thereof, ring D is anitrogen-linked saturated, partially-saturated or unsaturated 4-, 5-,6-, or 7-membered monocyclic ring, wherein each said ring contains 0, 1,2, 3, or 4 N atoms and 0, 1, or 2 atoms selected from O and S;independently substituted by 0, 1, 2 or 3 R⁹ groups selected from F, Cl,Br, C₁₋₆alk, C₁₋₄haloalk, —OR^(a), —OC₁₋₄haloalk, CN, —C(═O)R^(b),—C(═O)OR^(a), —C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a), —OC(═O)R^(b),—OC(═O)NR^(a)R^(a), —OC₂₋₆alkNR^(a)R^(a), —OC₂₋₆alkOR^(a), —SR^(a),—S(═O)R^(b), —S(═O)₂R^(b), —S(═O)₂NR^(a)R^(a), —NR^(a)R^(a),—N(R^(a))C(═O)R^(b), —N(R^(a))C(═O)OR^(b), —N(R^(a))C(═O)NR^(a)R^(a),—N(R^(a))C(═NR^(a))NR^(a)R^(a), —N(R^(a))S(═O)₂R^(b),—N(R^(a))S(═O)₂NR^(a)R^(a), —NR^(a)C₂₋₆alkNR^(a)R^(a),—NR^(a)C₂₋₆alkOR^(a), —C₁₋₆alkNR^(a)R^(a), —C₁₋₆alkOR^(a),—C₁₋₆alkN(R^(a))C(═O)R^(b), —C₁₋₆alkOC(═O)R^(b),—C₁₋₆alkC(═O)NR^(a)R^(a), —C₁₋₆alkC(═O)OR^(a) and oxo.

In another embodiment of the compound of formula (I), (II), (III), or(IV), or a pharmaceutically acceptable salt thereof, ring D is anitrogen-linked-saturated, partially-saturated or unsaturated 8-, 9-,10-, 11-, or 12-membered bicyclic ring, wherein each said ring contains0, 1, 2, 3, or 4 N atoms and 0, 1, or 2 atoms selected from O and S;independently substituted by 0, 1, 2 or 3 R⁹ groups selected from F, Cl,Br, C₁₋₆alk, C₁₋₄haloalk, —OR^(a), —OC₁₋₄haloalk, CN, —C(═O)R^(b),—C(═O)OR^(a), —C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a), —OC(═O)R^(b),—OC(═O)NR^(a)R^(a), —OC₂₋₆alkNR^(a)R^(a), —OC₂₋₆alkOR^(a), —SR^(a),—S(═O)R^(b), —S(═O)₂R^(b), —S(═O)₂NR^(a)R^(a), —NR^(a)R^(a),—N(R^(a))C(═O)R^(b), —N(R^(a))C(═O)OR^(b), —N(R^(a))C(═O)NR^(a)R^(a),—N(R^(a))C(═NR^(a))NR^(a)R^(a), —N(R^(a))S(═O)₂R^(b),—N(R^(a))S(═O)₂NR^(a)R^(a), —NR^(a)C₂₋₆alkNR^(a)R^(a),—NR^(a)C₂₋₆alkOR^(a), —C₁₋₆alkNR^(a)R^(a), —C₁₋₆alkOR^(a),—C₁₋₆alkN(R^(a))C(═O)R^(b), —C₁₋₆alkOC(═O)R^(b),—C₁₋₆alkC(═O)NR^(a)R^(a), —C₁₋₆alkC(═O)OR^(a) and oxo.

In another embodiment of the compound of formula (I), (II), (III), or(IV), or a pharmaceutically acceptable salt thereof, ring D iscyclohexyl, cyclopentyl, cyclopentenyl, cyclohexenyl, or cycloheptyl.

In another embodiment of the compound of formula (I), (II), (III), or(IV), or a pharmaceutically acceptable salt thereof, ring D isazetidinyl, phenyl, 2-pyridyl, 3-pyridyl, pyrazolyl, morpholinyl,pyrimidyl, piperazinyl, piperidinyl, dihydropyranyl, tetrahydropyranyl,tetrahydrofuranyl, tetrahydropyridinyl, or tetrahydrothiopyranyl.

In another embodiment of the compound of formula (I), (II), (III), or(IV), or a pharmaceutically acceptable salt thereof, ring D isoxaspiro[3.5]nonyl, azepanyl, oxepanyl, or quinolinyl.

In another embodiment of the compound of formula (I), (II), (III), or(IV), or a pharmaceutically acceptable salt thereof, ring D iscyclohexyl, cyclopentyl, cyclopentenyl, cyclohexenyl, cycloheptyl,azetidinyl, phenyl, 2-pyridyl, 3-pyridyl, pyrazolyl, morpholinyl,pyrimidyl, piperazinyl, piperidinyl, dihydropyranyl, tetrahydropyranyl,tetrahydrofuranyl, tetrahydropyridinyl, tetrahydrothiopyranyl,oxaspiro[3.5]nonyl, azepanyl, oxepanyl, or quinolinyl, all of which aresubstituted by 0, 1, 2 or 3 R⁹ groups selected from F, Cl, Br, C₁₋₆alk,C₁₋₄haloalk, —OR^(a), CN, —C(═O)R^(b), —C(═O)OR^(a), —NR^(a)R^(a),—SR^(a), and oxo.

Another aspect of the invention relates to a compound of formula (IV)having the formula:

wherein m, Ring D, R², R³, R^(4a), R^(4b), R⁵, Y, and X¹ are definedabove.

Another aspect of the invention relates to a compound having theformula:

wherein m, Ring D, R², R³, R^(4a), R^(4b), R⁵, Y, and X¹ are definedabove.

Another aspect of the invention relates to a compound having theformula:

wherein m, Ring D, R², R³, R^(4a), R^(4b), R⁵, Y, and X¹ are definedabove.

Another aspect of the invention relates to a method of treatingconditions that may be treated with PDE10 inhibitors comprising the stepof administering to a patient in need thereof a therapeuticallyeffective amount of any one of the above compounds, or apharmaceutically acceptable salt thereof.

In one embodiment of the method, said conditions is psychoses,Parkinson's disease, dementias, obsessive compulsive disorder, tardivedyskinesia, choreas, depression, mood disorders, impulsivity, drugaddiction, attention deficit/hyperactivity disorder (ADHD), depressionwith parkinsonian states, personality changes with caudate or putamendisease, dementia and mania with caudate and pallidal diseases, orcompulsions with pallidal disease.

In another embodiment of the method, said condition is schizophrenia,Huntington's disease, bipolar disorder, or obsessive-compulsivedisorder.

In another embodiment of the method, said condition is schizophrenia.

Another aspect of the invention relates to a pharmaceutical compositioncomprising any one of the above compounds, or a pharmaceuticallyacceptable salt thereof, and a pharmaceutically-acceptable excipient.

Another aspect of the invention relates to the use of any one of theabove compounds, or a pharmaceutically acceptable salt thereof, as amedicament.

Another aspect of the invention relates to the use of any one of theabove compounds, or a pharmaceutically acceptable salt thereof in themanufacture of a medicament for the treatment of schizophrenia, bipolardisorder, or obsessive-compulsive disorder.

Another aspect of the invention relates to a compound, or apharmaceutically acceptable salt thereof, which is tabulated below:

Chemical Structure Chemical Name

(1H-Benzoimidazol-2-yl)-[3-(3-phenyl-pyridin-2-yl)-azetidin-1-yl]-methanone

(1H-Benzoimidazol-2-yl)-[3-(5-fluoro-3-phenyl-pyridin-2-yl)-azetidin-1-yl]- methanone

(1H-benzoimidazol-2-yl)-[4-(3-phenyl-pyrazin-2-yl)-piperidin-1-yl]-methanone

Benzothiazol-2-yl-[3-(3-phenyl-pyrazin-2- yl)-azetidin-1-yl]-methanone

(1H-Benzoimidazol-2-yl)-[3-(3-piperidin-1-yl-quinoxalin-2-yl)-azetidin-1-yl]- methanone

(1H-Benzoimidazol-2-yl)-{3-[3-(4-hydroxy-piperidin-1-yl)-quinoxalin-2-yl]- azetidin-1-yl}-methanone

(1H-Benzoimidazol-2-yl)-[3-(2,3-dihydro-indol-1-yl)-3′,4′,5′,6′-tetrahydro-2′H-[2,4′]bipyridinyl-1′-yl]-methanone

(1H-Benzoimidazol-2-yl)-[3-(3-phenyl-quinolin-2-yl)-azetidin-1-yl]-methanone

(1H-Benzoimidazol-2-yl)-(3-phenyl-3′,4′,5′,6′-tetrahydro-2′H-[2,4′]bipyridinyl- 1′-yl)-methanone

(1H-Benzoimidazol-2-yl)-{4-[3-(4-hydroxymethyl-piperidin-1-yl)-pyrazin-2- yl]-piperidin-1-yl}-methanone

(3-(3-phenylpyrazin-2-yl)azetidin-1- yl)(pyridin-2-yl)methanone

(6-methylpyridin-2-yl)(3-(3- phenylpyrazin-2-yl)azetidin-1- yl)methanone

(3-methylpyridin-2-yl)(3-(3- phenylpyrazin-2-yl)azetidin-1- yl)methanone

(5-methylpyridin-2-yl)(3-(3- phenylpyrazin-2-yl)azetidin-1- yl)methanone

(4-methylpyridin-2-yl)(3-(3- phenylpyrazin-2-yl)azetidin-1- yl)methanone

(1H-Benzoimidazol-2-yl)-[3-(3-phenyl-quinoxalin-2-yl)-azetidin-1-yl]-methanone

(1H-Benzoimidazol-2-yl)-[3-(3-morpholin-4-yl-pyrazin-2-yl)-azetidin-1-yl]- methanone

(1-Methyl-1H-benzoimidazol-2-yl)-[3-(3-phenyl-pyrazin-2-yl)-azetidin-1-yl]- methanone

[3-(3-Phenyl-pyrazin-2-yl)-azetidin-1-yl]-[1-(2,2,2-trifluoro-ethyl)-1H- benzoimidazol-2-yl]-methanone

(1H-Benzoimidazol-2-yl)-[3-(3-phenyl-pyrazin-2-yl)-azetidin-1-yl]-methanone

(1H-Benzoimidazol-2-yl)-{3-[3-(3,4-dimethoxy-phenyl)-pyrazin-2-yl]-azetidin- 1-yl}-methanone

(1H-Benzoimidazol-2-yl)-{3-[3-(3-isopropyl-phenyl)-pyrazin-2-yl]-azetidin- 1-yl}-methanone

(1H-Benzoimidazol-2-yl)-{3-[3-(3-trifluoromethoxy-phenyl)-pyrazin-2-yl]- azetidin-1-yl}-methanone

1H-Benzoimidazol-2-yl)-{3-[3-(3,5-dimethoxy-phenyl)-pyrazin-2-yl]-azetidin- 1-yl}-methanone

(1H-Benzoimidazol-2-yl)-{3-[3-(3-ethoxy-phenyl)-pyrazin-2-yl]-azetidin-1-yl}- methanone

(1H-Benzoimidazol-2-yl)-{3-[3-(3-isopropoxy-phenyl)-pyrazin-2-yl]-azetidin- 1-yl}-methanone

(1H-Benzoimidazol-2-yl)-{3-[3-(3-fluoro-5-methoxy-phenyl)-pyrazin-2-yl]-azetidin- 1-yl}-methanone

(1H-Benzoimidazol-2-yl)-{3-[3-(2- methoxy-pyridin-4-yl)-pyrazin-2-yl]-azetidin-1-yl}-methanone

(1H-Benzoimidazol-2-yl)-{3-[3-(5- methoxy-pyridin-3-yl)-pyrazin-2-yl]-azetidin-1-yl}-methanone

(1H-benzo[d]imidazol-2-yl)(3-(3-(4- fluoro-3-methylphenyl)pyrazin-2-yl)azetidin-1-yl)methanone

(1H-Benzoimidazol-2-yl)-{3-[3-(4-methoxy-3-methyl-phenyl)-pyrazin-2-yl]- azetidin-1-yl}-methanone

(1H-Benzoimidazol-2-yl)-{3-[3-(3-fluoro-5-methyl-phenyl)-pyrazin-2-yl]-azetidin-1- yl}-methanone

(1H-Benzoimidazol-2-yl)-{3-[3-(5-methyl-pyridin-3-yl)-pyrazin-2-yl]-azetidin-1-yl}- methanone

(1H-Benzoimidazol-2-yl)-{3-[3-(4-methyl-thiophen-2-yl)-pyrazin-2-yl]-azetidin-1- yl}-methanone

(1H-Benzoimidazol-2-yl)-{3-[3-(1-methyl-1H-pyrazol-4-yl)-pyrazin-2-yl]-azetidin-1- yl}-methanone

(1H-Benzoimidazol-2-yl)-{3-[3-(3- hydroxymethyl-phenyl)-pyrazin-2-yl]-azetidin-1-yl}-methanone

(1H-Benzoimidazol-2-yl)-{3-[3-(4- hydroxymethyl-phenyl)-pyrazin-2-yl]-azetidin-1-yl}-methanone

1-(4-{3-[1-(1H-Benzoimidazole-2- carbonyl)-azetidin-3-yl]-pyrazin-2-yl}-phenyl)-ethanone

1-(3-{3-[1-(1H-Benzoimidazole-2- carbonyl)-azetidin-3-yl]-pyrazin-2-yl}-phenyl)-ethanone

(1H-Benzoimidazol-2-yl)-{3-[3-(3- methoxymethyl-phenyl)-pyrazin-2-yl]-azetidin-1-yl}-methanone

4-{3-[1-(1H-Benzoimidazole-2-carbonyl)-azetidin-3-yl]-pyrazin-2-yl}-N,N- dimethyl-benzamide

3-{3-[1-(1H-Benzoimidazole-2-carbonyl)-azetidin-3-yl]-pyrazin-2-yl}-N,N- dimethyl-benzamide

(1H-benzo[d]imidazol-2-yl)(3-(3-(pyridin-4-yl)pyrazin-2-yl)azetidin-1-yl)methanone

(7-chloro-1H-benzo[d]imidazol-2-yl)(3-(3-(pyridin-3-yl)pyrazin-2-yl)azetidin-1- yl)methanone

(1H-benzo[d]imidazol-2-yl)(3-(3-(2-methylpyridin-4-yl)pyrazin-2-yl)azetidin- 1-yl)methanone

(1H-benzo[d]imidazol-2-yl)(3-(3-(m-tolyl)pyrazin-2-yl)azetidin-1-yl)methanone

3-(3-(1-(1H-benzo[d]imidazole-2- carbonyl)azetidin-3-yl)pyrazin-2-yl)benzonitrile

(1-Methyl-1H-benzoimidazol-2-yl)-[3-(3-piperidin-1-yl-pyrazin-2-yl)-azetidin-1-yl]- methanone

{3-[3-(4-Hydroxy-piperidin-1-yl)-pyrazin-2-yl]-azetidin-1-yl}-(1-methyl-1H- benzoimidazol-2-yl)-methanone

[3-(3-Piperidin-1-yl-pyrazin-2-yl)-azetidin-1-yl]-[1-(2,2,2-trifluoro-ethyl)-1H- benzoimidazol-2-yl]-methanone

{3-[3-(4-Hydroxy-piperidin-1-yl)-pyrazin-2-yl]-azetidin-1-yl}-[1-(2,2,2-trifluoro-ethyl)-1H-benzoimidazol-2-yl]-methanone

(1H-Benzoimidazol-2-yl)-[3-(3-pyrrolidin-1-yl-pyrazin-2-yl)-azetidin-1-yl]- methanone

(1H-Benzoimidazol-2-yl)-{3-[3-(4-trifluoromethyl-piperidin-1-yl)-pyrazin-2- yl]-azetidin-1-yl}-methanone

(R & S)-(1H-Benzoimidazol-2-yl)-{3-[3-(2-methyl-piperidin-1-yl)-pyrazin-2-yl]- azetidin-1-yl}-methanone

(1H-Benzoimidazol-2-yl)-{3-[3-(3-methyl-piperidin-1-yl)-pyrazin-2-yl]-azetidin-1- yl}-methanone

(1H-Benzoimidazol-2-yl)-{3-[3-(4-methyl-piperidin-1-yl)-pyrazin-2-yl]-azetidin-1- yl}-methanone

(1H-Benzoimidazol-2-yl)-{3-[3-(4,4-dimethyl-piperidin-1-yl)-pyrazin-2-yl]- azetidin-1-yl}-methanone

(1H-Benzoimidazol-2-yl)-{3-[3-(4-hydroxymethyl-piperidin-1-yl)-pyrazin-2- yl]-azetidin-1-yl}-methanone

(1H-Benzoimidazol-2-yl)-(3-{3-[4-(1-hydroxy-1-methyl-ethyl)-piperidin-1-yl]-pyrazin-2-yl}-azetidin-1-yl)-methanone

(1H-Benzoimidazol-2-yl)-(3-{3-[4-(1-hydroxy-1-methyl-ethyl)-piperidin-1-yl]-pyrazin-2-yl}-azetidin-1-yl)-methanone

1-{3-[1-(1H-Benzoimidazole-2-carbonyl)-azetidin-3-yl]-pyrazin-2-yl}-piperidine-4- carbonitrile

(1H-Benzoimidazol-2-yl)-{3-[3-(4-methoxymethyl-piperidin-1-yl)-pyrazin-2- yl]-azetidin-1-yl}-methanone

(R & S)-(1H-Benzoimidazol-2-yl)-{3-[3-(3-methyl-pyrrolidin-1-yl)-pyrazin-2-yl]- azetidin-1-yl}-methanone

(R & S)-(1H-Benzoimidazol-2-yl)-{3-[3-(2-methyl-pyrrolidin-1-yl)-pyrazin-2-yl]- azetidin-1-yl}-methanone

(1H-Benzoimidazol-2-yl)-{3-[3-(3,4-dihydro-1H-isoquinolin-2-yl)-pyrazin-2- yl]-azetidin-1-yl}-methanone

(1H-Benzoimidazol-2-yl)-{3-[3-(1,3-dihydro-isoindol-2-yl)-pyrazin-2-yl]- azetidin-1-yl}-methanone

(R & S)-(1H-Benzoimidazol-2-yl)-{3-[3-(3-phenyl-pyrrolidin-1-yl)-pyrazin-2-yl]- azetidin-1-yl}-methanone

(R & S)-(1H-Benzoimidazol-2-yl)-{3-[3-(2-phenyl-pyrrolidin-1-yl)-pyrazin-2-yl]- azetidin-1-yl}-methanone

(1H-Benzoimidazol-2-yl)-[3-(3- cyclopentylamino-pyrazin-2-yl)-azetidin-1-yl]-methanone

(1H-Benzoimidazol-2-yl)-[3-(3- cyclohexylamino-pyrazin-2-yl)-azetidin-1-yl]-methanone

(1H-Benzoimidazol-2-yl)-[3-(3- benzylamino-pyrazin-2-yl)-azetidin-1-yl]-methanone

(1H-Benzoimidazol-2-yl)-{3-[3-(2- hydroxy-ethylamino)-pyrazin-2-yl]-azetidin-1-yl}-methanone

(1H-benzo[d]imidazol-2-yl)(3-(3-((2- methoxyethyl)amino)pyrazin-2-yl)azetidin-1-yl)methanone

1-{3-[1-(1H-Benzoimidazole-2-carbonyl)-azetidin-3-yl]-pyrazin-2-yl}-piperidine-4- carboxylic acid amide

(R & S)-(1H-Benzoimidazol-2-yl)-{3-[3-(3-hydroxymethyl-piperidin-1-yl)-pyrazin- 2-yl]-azetidin-1-yl}-methanone

(1H-Benzoimidazol-2-yl)-{3-[3-(3- hydroxy-piperidin-1-yl)-pyrazin-2-yl]-azetidin-1-yl}-methanone

[3-(3-Azepan-1-yl-pyrazin-2-yl)-azetidin-1-yl]-(1H-benzoimidazol-2-yl)-methanone

[3-(3-Azetidin-1-yl-pyrazin-2-yl)-azetidin-1-yl]-(1H-benzoimidazol-2-yl)-methanone

(R)-(1H-Benzoimidazol-2-yl)-{3-[3-(2-hydroxymethyl-pyrrolidin-1-yl)-pyrazin-2- yl]-azetidin-1-yl}-methanone

(1H-Benzoimidazol-2-yl)-[3-(3- isopropylamino-pyrazin-2-yl)-azetidin-1-yl]-methanone

(S)-(1H-Benzoimidazol-2-yl)-{3-[3-(2-hydroxymethyl-pyrrolidin-1-yl)-pyrazin-2- yl]-azetidin-1-yl}-methanone

(1H-Benzoimidazol-2-yl)-(3-{3-[4-(2-hydroxy-ethyl)-piperidin-1-yl]-pyrazin-2- yl}-azetidin-1-yl)-methanone

(1H-Benzoimidazol-2-yl)-[3-(3-[1,4]oxazepan-4-yl-pyrazin-2-yl)-azetidin- 1-yl]-methanone

(1H-Benzoimidazol-2-yl)-{3-[3-(4-methyl-[1,4]diazepan-1-yl)-pyrazin-2-yl]-azetidin- 1-yl}-methanone

1-(4-{3-[1-(1H-Benzoimidazole-2- carbonyl)-azetidin-3-yl]-pyrazin-2-yl}-[1,4]diazepan-1-yl)-ethanone

(1H-Benzoimidazol-2-yl)-{3-[3-(4- hydroxy-azepan-1-yl)-pyrazin-2-yl]-azetidin-1-yl}-methanone

(R & S)-(1H-Benzoimidazol-2-yl)-{3-[3-(3-hydroxymethyl-pyrrolidin-1-yl)-pyrazin-2-yl]-azetidin-1-yl}-methanone

(R)-(1H-Benzoimidazol-2-yl)-{3-[3-(3-hydroxy-piperidin-1-yl)-pyrazin-2-yl]- azetidin-1-yl}-methanone

(S)-(1H-Benzoimidazol-2-yl)-{3-[3-(3-hydroxy-piperidin-1-yl)-pyrazin-2-yl]- azetidin-1-yl}-methanone

(R & S)-1-{3-[1-(1H-Benzoimidazole-2-carbonyl)-azetidin-3-yl]-pyrazin-2-yl}- piperidine-3-carbonitrile

1-{3-[1-(1H-Benzoimidazole-2-carbonyl)-azetidin-3-yl]-pyrazin-2-yl}-piperidine-4- carboxylic acid methylamide

1-{3-[1-(1H-Benzoimidazole-2-carbonyl)-azetidin-3-yl]-pyrazin-2-yl}-piperidine-4- carboxylic acid dimethylamide

1-(1-(3-(1-(1H-benzo[d]imidazole-2- carbonyl)azetidin-3-yl)pyrazin-2-yl)piperidin-4-yl)ethanone

1-(4-(3-(1-(1H-benzo[d]imidazole-2- carbonyl)azetidin-3-yl)pyrazin-2-yl)piperazin-1-yl)ethanone

(R)-(1H-benzo[d]imidazol-2-yl)(3-(3-(3-hydroxypyrrolidin-1-yl)pyrazin-2- yl)azetidin-1-yl)methanone

(S)-(1H-benzo[d]imidazol-2-yl)(3-(3-(3-hydroxypyrrolidin-1-yl)pyrazin-2- yl)azetidin-1-yl)methanone

(1H-benzo[d]imidazol-2-yl)(3-(3-(piperidin-1-yl)pyrazin-2-yl)azetidin-1- yl)methanone

(1H-benzo[d]imidazol-2-yl)(3-(3-(4- hydroxypiperidin-1-yl)pyrazin-2-yl)azetidin-1-yl)methanone

(1H-Benzoimidazol-2-yl)-{3-[3-(2-oxa-7-aza-spiro[3.5]non-7-yl)-pyrazin-2-yl]- azetidin-1-yl}-methanone

(1H-Benzoimidazol-2-yl)-{3-[3-(2-oxa-6-aza-spiro[3.3]hept-6-yl)-pyrazin-2-yl]- azetidin-1-yl}-methanone

1-(6-{3-[1-(1H-Benzoimidazole-2-carbonyl)-azetidin-3-yl]-pyrazin-2-yl}-2,6-diaza-spiro[3.3]hept-2-yl)-ethanone

2-(3-(3-(2-methoxypyridin-3-yl)pyrazin-2- yl)azetidin-1-yl)quinoline

2-(3-(3-(6-methylpyridin-3-yl)pyrazin-2- yl)azetidin-1-yl)quinoline

2-(3-(3-(2-methylpyridin-3-yl)pyrazin-2- yl)azetidin-1-yl)quinoline

2-(3-(3-(6-fluoropyridin-3-yl)pyrazin-2- yl)azetidin-1-yl)quinoline

2-(3-(3-(6-(trifluoromethyl)pyridin-3-yl)pyrazin-2-yl)azetidin-1-yl)quinoline

2-(3-(3-(2,6-dimethoxypyridin-3- yl)pyrazin-2-yl)azetidin-1-yl)quinoline

2-(3-(3-(5-fluoropyridin-3-yl)pyrazin-2- yl)azetidin-1-yl)quinoline

2-(3-(3-(6-methoxypyridin-3-yl)pyrazin-2- yl)azetidin-1-yl)quinoline2,2,2- trifluoroacetate

2-(3-(3-(6-fluoro-5-methylpyridin-3-yl)pyrazin-2-yl)azetidin-1-yl)quinoline 2,2,2-trifluoroacetate

2-(3-(3-(pyridin-3-yl)pyrazin-2- yl)azetidin-1-yl)quinoline 2,2,2-trifluoroacetate

2-(3-(3-(4- (methylsulfonyl)phenyl)pyrazin-2- yl)azetidin-1-yl)quinoline2,2,2- trifluoroacetate

5-(3-(1-(quinolin-2-yl)azetidin-3- yl)pyrazin-2-yl)pyridin-2-amine

5-(3-(1-(quinolin-2-yl)azetidin-3- yl)pyrazin-2-yl)pyridin-3-amine

2-(3-(3-(6-methoxypyridin-2-yl)pyrazin-2- yl)azetidin-1-yl)quinoline

2-(3-(3-(2-(trifluoromethyl)pyridin-3-yl)pyrazin-2-yl)azetidin-1-yl)quinoline 2,2,2-trifluoroacetate

N,N-dimethyl-5-(3-(1-(quinolin-2-yl)azetidin-3-yl)pyrazin-2-yl)pyrimidin-2- amine 2,2,2-trifluoroacetate

2-(3-(3-(4-methylpyridin-3-yl)pyrazin-2- yl)azetidin-1-yl)quinoline2,2,2- trifluoroacetate

2-(3-(3-(5-(methylsulfonyl)pyridin-3-yl)pyrazin-2-yl)azetidin-1-yl)quinoline 2,2,2-trifluoroacetate

2-(3-(3-(5-methylpyridin-3-yl)pyrazin-2- yl)azetidin-1-yl)quinoline2,2,2- trifluoroacetate

2-(3-(3-(5-methoxypyridin-3-yl)pyrazin-2- yl)azetidin-1-yl)quinoline2,2,2- trifluoroacetate

2-(3-(3-(4-chloro-3-methylphenyl)pyrazin- 2-yl)azetidin-1-yl)quinoline

2-(3-(3-(3-fluoro-4-methylphenyl)pyrazin- 2-yl)azetidin-1-yl)quinoline

2-chloro-4-(3-(1-(quinolin-2-yl)azetidin-3- yl)pyrazin-2-yl)phenol

2-(3-(3-(3-methoxy-5- (trifluoromethyl)phenyl)pyrazin-2-yl)azetidin-1-yl)quinoline

2-(3-(3-(4-ethoxy-3-fluorophenyl)pyrazin- 2-yl)azetidin-1-yl)quinoline

2-(3-(3-(3-chloro-4-ethoxyphenyl)pyrazin- 2-yl)azetidin-1-yl)quinoline

2-(3-(3-(3-chloro-4- propoxyphenyl)pyrazin-2-yl)azetidin-1- yl)quinoline

2-(3-(3-(3-fluoro-5- (trifluoromethyl)phenyl)pyrazin-2-yl)azetidin-1-yl)quinoline

2-(3-(3-(4-methoxy-3- methylphenyl)pyrazin-2-yl)azetidin-1- yl)quinoline

2-(3-(3-(3-fluoro-5- isopropoxyphenyl)pyrazin-2-yl)azetidin-1-yl)quinoline

2-(3-(3-(3-fluoro-5-methylphenyl)pyrazin- 2-yl)azetidin-1-yl)quinoline

2-(3-(3-(3-chloro-4-fluorophenyl)pyrazin- 2-yl)azetidin-1-yl)quinoline

2-(3-(3-(3,4-difluorophenyl)pyrazin-2- yl)azetidin-1-yl)quinoline

2-(3-(3-(3,4-dichlorophenyl)pyrazin-2- yl)azetidin-1-yl)quinoline

2-(3-(3-(3,4-dimethylphenyl)pyrazin-2- yl)azetidin-1-yl)quinoline

2-(3-(3-(3-chloro-4-methylphenyl)pyrazin- 2-yl)azetidin-1-yl)quinoline

2-(3-(3-(3-chloro-5-methylphenyl)pyrazin- 2-yl)azetidin-1-yl)quinoline

2-(3-(3-(4-fluoro-3-methylphenyl)pyrazin- 2-yl)azetidin-1-yl)quinoline

2-(3-(3-(pyrimidin-5-yl)pyrazin-2- yl)azetidin-1-yl)quinoline

2-(3-(3-(4-chloro-3- (trifluoromethyl)phenyl)pyrazin-2-yl)azetidin-1-yl)quinoline

2-(3-(3-(3,6-dihydro-2H-pyran-4- yl)pyrazin-2-yl)azetidin-1-yl)quinoline

2-(3-(3-(2,2-dimethyl-3,6-dihydro-2H-pyran-4-yl)pyrazin-2-yl)azetidin-1- yl)quinoline and2-(3-(3-(6,6-dimethyl-3,6- dihydro-2H-pyran-4-yl)pyrazin-2-yl)azetidin-1-yl)quinoline

2-(3-(3-(1H-pyrazol-4-yl)pyrazin-2- yl)azetidin-1-yl)quinoline

2-(3-(3-(3-fluoro-5- (trifluoromethyl)phenyl)pyrazin-2-yl)azetidin-1-yl)quinoline

2-(3-(3-(6-methoxypyridin-2-yl)pyrazin-2- yl)azetidin-1-yl)quinoline

2-(3-(3-phenylpyrazin-2-yl)azetidin-1- yl)quinoline

2-(3-(3-(4-methoxyphenyl)pyrazin-2- yl)azetidin-1-yl)quinoline

2-(3-(3-(4-fluorophenyl)pyrazin-2- yl)azetidin-1-yl)quinoline

2-(3-(3-(2-fluorophenyl)pyrazin-2- yl)azetidin-1-yl)quinoline

2-(3-(3-(3-fluorophenyl)pyrazin-2- yl)azetidin-1-yl)quinoline

2-(3-(3-(pyridin-4-yl)pyrazin-2- yl)azetidin-1-yl)quinoline

3-(3-(1-(quinolin-2-yl)azetidin-3- yl)pyrazin-2-yl)benzonitrile

4-(3-(1-(quinolin-2-yl)azetidin-3- yl)pyrazin-2-yl)benzonitrile

methyl 3-(3-(1-(quinolin-2-yl)azetidin-3- yl)pyrazin-2-yl)benzoate

ethyl 4-(3-(1-(quinolin-2-yl)azetidin-3- yl)pyrazin-2-yl)benzoate

2-(3-(3-(2-methoxypyridin-4-yl)pyrazin-2- yl)azetidin-1-yl)quinoline

2-(3-(3-(2-fluoropyridin-4-yl)pyrazin-2- yl)azetidin-1-yl)quinoline

2-(3-(3-(3-(methylthio)phenyl)pyrazin-2- yl)azetidin-1-yl)quinoline

1-(4-(3-(1-(quinolin-2-yl)azetidin-3- yl)pyrazin-2-yl)phenyl)ethanone

2-(3-(3-(4-phenoxyphenyl)pyrazin-2- yl)azetidin-1-yl)quinoline

2-(3-(3-(4- (trifluoromethyl)phenyl)pyrazin-2-yl)azetidin-1-yl)quinoline

2-(3-(3-(3-fluoro-4- methoxyphenyl)pyrazin-2-yl)azetidin-1- yl)quinoline

N,N-dimethyl-3-(3-(1-(quinolin-2- yl)azetidin-3-yl)pyrazin-2-yl)aniline

N-methyl-3-(3-(1-(quinolin-2-yl)azetidin- 3-yl)pyrazin-2-yl)benzamide

tert-butyl 4-(3-(1-(quinolin-2-yl)azetidin-3-yl)pyrazin-2-yl)-5,6-dihydropyridine- 1(2H)-carboxylate

2-(3-(3-([1,1′-biphenyl]-3-yl)pyrazin-2- yl)azetidin-1-yl)quinoline

2-fluoro-4-(3-(1-(quinolin-2-yl)azetidin-3- yl)pyrazin-2-yl)benzonitrile

2-fluoro-5-(3-(1-(quinolin-2-yl)azetidin-3- yl)pyrazin-2-yl)benzonitrile

N,N-dimethyl-3-(3-(1-(quinolin-2-yl)azetidin-3-yl)pyrazin-2-yl)benzamide

2-(3-(3-(2-methoxyphenyl)pyrazin-2- yl)azetidin-1-yl)quinoline

2-(3-(3-(3- (trifluoromethyl)phenyl)pyrazin-2-yl)azetidin-1-yl)quinoline

2-(3-(3-(3-ethoxyphenyl)pyrazin-2- yl)azetidin-1-yl)quinoline

1-(3-(3-(1-(quinolin-2-yl)azetidin-3- yl)pyrazin-2-yl)phenyl)ethanone

(3-(3-(1-(quinolin-2-yl)azetidin-3- yl)pyrazin-2-yl)phenyl)methanol

2-(3-(3-(3- (trifluoromethoxy)phenyl)pyrazin-2-yl)azetidin-1-yl)quinoline

2-(3-(3-(3-(benzyloxy)phenyl)pyrazin-2- yl)azetidin-1-yl)quinoline

N-cyclopropyl-3-(3-(1-(quinolin-2-yl)azetidin-3-yl)pyrazin-2-yl)benzamide

N,N-dimethyl-3-(3-(1-(quinolin-2- yl)azetidin-3-yl)pyrazin-2-yl)benzenesulfonamide

2-(3-(3-(4-ethoxyphenyl)pyrazin-2- yl)azetidin-1-yl)quinoline

(4-(3-(1-(quinolin-2-yl)azetidin-3- yl)pyrazin-2-yl)phenyl)methanol

2-(3-(3-(4-propylphenyl)pyrazin-2- yl)azetidin-1-yl)quinoline

2-(3-(3-(4-ethylphenyl)pyrazin-2- yl)azetidin-1-yl)quinoline

N,N-dimethyl-4-(3-(1-(quinolin-2- yl)azetidin-3-yl)pyrazin-2-yl)aniline

2-(3-(3-(4- (trifluoromethoxy)phenyl)pyrazin-2-yl)azetidin-1-yl)quinoline

2-(3-(3-(4-isopropoxyphenyl)pyrazin-2- yl)azetidin-1-yl)quinoline

2-methyl-2-(4-(3-(1-(quinolin-2- yl)azetidin-3-yl)pyrazin-2-yl)phenyl)propanenitrile

4-((4-(3-(1-(quinolin-2-yl)azetidin-3- yl)pyrazin-2-yl)phenyl)sulfonyl)morpholine

2-(3-(3-(4-(piperidin-1- ylsulfonyl)phenyl)pyrazin-2-yl)azetidin-1-yl)quinoline

(R- & S-)-2-(3-(3-(3-(pyridin-3-yl)pyrrolidin-1-yl)pyrazin-2-yl)azetidin-1- yl)quinoline

(R- & S-)-2-(3-(3-(3-phenethylpyrrolidin-1-yl)pyrazin-2-yl)azetidin-1-yl)quinoline

(R- & S-)-2-(3-(3-(3-benzylpyrrolidin-1-yl)pyrazin-2-yl)azetidin-1-yl)quinoline

(R)-N,N-dimethyl-1-(3-(1-(quinolin-2-yl)azetidin-3-yl)pyrazin-2-yl)pyrrolidin-3- amine

(R- & S-)-tert-butyl methyl(1-(3-(1-(quinolin-2-yl)azetidin-3-yl)pyrazin-2- yl)pyrrolidin-3-yl)carbamate

(R- & S-)-N,N-dimethyl-1-(3-(1-(quinolin-2-yl)azetidin-3-yl)pyrazin-2-yl)pyrrolidin- 3-amine

2-(3-(3-(3-azabicyclo[3.1.0]hexan-3-yl)pyrazin-2-yl)azetidin-1-yl)quinoline

(R- & S-)-2-(3-(3-(3- (phenylsulfonyl)pyrrolidin-1-yl)pyrazin-2-yl)azetidin-1-yl)quinoline

(R- & S-)-3-methyl-5-(1-(3-(1-(quinolin-2-yl)azetidin-3-yl)pyrazin-2-yl)pyrrolidin-3- yl)-1,2,4-oxadiazole

(R)-1-(3-(1-(quinolin-2-yl)azetidin-3- yl)pyrazin-2-yl)pyrrolidin-3-ol

(R- & S-)-2-(3-(3-(3-(pyridin-4-yl)pyrrolidin-1-yl)pyrazin-2-yl)azetidin-1- yl)quinoline

2-(3-(3-(pyrrolidin-1-yl)pyrazin-2- yl)azetidin-1-yl)quinoline

(3aR,6aS)-tert-butyl 5-(3-(1-(quinolin-2- yl)azetidin-3-yl)pyrazin-2-yl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)- carboxylate

tert-butyl 5-(3-(1-(quinolin-2-yl)azetidin-3-yl)pyrazin-2-yl)hexahydropyrrolo[3,4- c]pyrrole-2(1H)-carboxylate

tert-butyl 4-(3-(1-(quinolin-2-yl)azetidin-3-yl)pyrazin-2-yl)-1,4-diazepane-1- carboxylate

(R)-(1-(3-(1-(quinolin-2-yl)azetidin-3-yl)pyrazin-2-yl)pyrrolidin-3-yl)methanol

(R- & S-)-2-(3-(3-(3- (methylsulfonyl)pyrrolidin-1-yl)pyrazin-2-yl)azetidin-1-yl)quinoline

(S)-(1-(3-(1-(quinolin-2-yl)azetidin-3-yl)pyrazin-2-yl)pyrrolidin-3-yl)methanol

(R)-tert-butyl 1-(3-(1-(quinolin-2-yl)azetidin-3-yl)pyrazin-2-yl)pyrrolidin-3- ylcarbamate

(S)-2-(3-(3-(3-fluoropyrrolidin-1-yl)pyrazin-2-yl)azetidin-1-yl)quinoline

2-(3-(3-(3,3-difluoropyrrolidin-1-yl)pyrazin-2-yl)azetidin-1-yl)quinoline

2-(3-(3-(4-isopropyl-1,4-diazepan-1-yl)pyrazin-2-yl)azetidin-1-yl)quinoline

(1R,5R)-3-(3-(1-(quinolin-2-yl)azetidin-3-yl)pyrazin-2-yl)-3-azabicyclo[3.2.2]nonane

2-(3-(3-(azepan-1-yl)pyrazin-2-yl)azetidin- 1-yl)quinoline

2-(3-(3-(4-methyl-1,4-diazepan-1-yl)pyrazin-2-yl)azetidin-1-yl)quinoline

3-(3-(1-(quinolin-2-yl)azetidin-3-yl)pyrazin-2-yl)-3-azabicyclo[3.2.2]nonane

1-(4-(3-(1-(quinolin-2-yl)azetidin-3- yl)pyrazin-2-yl)-1,4-diazepan-1-yl)ethanone

(R- & S-)-2-(3-(3-(3-phenylpyrrolidin-1-yl)pyrazin-2-yl)azetidin-1-yl)quinoline

(3S,4S)-1-(3-(1-(quinolin-2-yl)azetidin-3-yl)pyrazin-2-yl)pyrrolidine-3,4-diol

N-(4-methoxybenzyl)-3-(1-(quinolin-2- yl)azetidin-3-yl)pyrazin-2-amine

(1R,4R)-5-(3-(1-(quinolin-2-yl)azetidin-3- yl)pyrazin-2-yl)-2-oxa-5-azabicyclo[2.2.1]heptane

(R- & S-)-2-(1-(3-(1-(quinolin-2-yl)azetidin-3-yl)pyrazin-2-yl)pyrrolidin-3- yl)thiazole

(S)-(1-(3-(1-(quinolin-2-yl)azetidin-3-yl)pyrazin-2-yl)pyrrolidin-2-yl)methanol

((2S,4S)-4-fluoro-1-(3-(1-(quinolin-2-yl)azetidin-3-yl)pyrazin-2-yl)pyrrolidin-2- yl)methanol

(R)-2-(3-(3-(2-(methoxymethyl)pyrrolidin-1-yl)pyrazin-2-yl)azetidin-1-yl)quinoline

2-(3-(3-(hexahydrocyclopenta[c]pyrrol-2(1H)-yl)pyrazin-2-yl)azetidine-1- yl)quinoline

(R- & S-)-2-(3-(3-(3-isobutylpyrrolidin-1-yl)pyrazin-2-yl)azetidin-1-yl)quinoline

2-(3-(3-(3,3-dimethylpyrrolidin-1-yl)pyrazin-2-yl)azetidin-1-yl)quinoline

(R- & S-)-2-(3-(3-(3- (methoxymethyl)pyrrolidin-1-yl)pyrazin-2-yl)azetidin-1-yl)quinoline

2-(3-(4-(trifluoromethyl)piperidin-1-yl)pyrazin-2-yl)azetidin-1-yl)quinoline

1-(3-(1-(quinolin-2-yl)azetidin-3-yl)pyrazin-2-yl)piperidine-4-carbonitrile

2-(3-(3-(4,4-difluoropiperidin-1-yl)pyrazin-2-yl)azetidin-1-yl)quinoline

4-(3-(1-(quinolin-2-yl)azetidin-3- yl)pyrazin-2-yl)morpholine

2-(3-(3-(4-fluoropiperidin-1-yl)pyrazin-2- yl)azetidin-1-yl)quinoline

2-(3-(3-(3-methoxyazetidin-1-yl)pyrazin- 2-yl)azetidin-1-yl)quinoline

2-(3-(3-(3,3-difluoroazetidin-1-yl)pyrazin- 2-yl)azetidin-1-yl)quinoline

4-methyl-1-(3-(1-(quinolin-2-yl)azetidin-3-yl)pyrazin-2-yl)piperidin-4-ol

1-(3-(1-(quinolin-2-yl)azetidin-3- yl)pyrazin-2-yl)-1H-pyrazole-4-carbonitrile

2-(3-(3-(4-methyl-1H-pyrazol-1- yl)pyrazin-2-yl)azetidin-1-yl)quinoline

tert-butyl (1-(3-(1-(quinolin-2-yl)azetidin-3-yl)pyrazin-2-yl)azetidin-3-yl)carbamate

2,2-dimethyl-4-(3-(1-(quinolin-2-yl)azetidin-3-yl)pyrazin-2-yl)morpholine

2-(3-(3-(4-methyl-1H-imidazol-1- yl)pyrazin-2-yl)azetidin-1-yl)quinoline

1-(3-(1-(quinazolin-2-yl)azetidin-3-yl)pyrazin-2-yl)piperidine-4-carbonitrile

(1-(3-(1-(quinolin-2-yl)azetidin-3-yl)pyrazin-2-yl)-1H-pyrazol-4-yl)methanol

(1-(3-(1-(quinolin-2-yl)azetidin-3- yl)pyrazin-2-yl)-1H-imidazol-4-yl)methanol

1-methyl-4-(3-(1-(quinolin-2-yl)azetidin-3-yl)pyrazin-2-yl)piperazin-2-one

N-(2,6-dimethylphenyl)-1-(3-(1-(quinolin-2-yl)azetidin-3-yl)pyrazin-2-yl)piperidine- 3-carboxamide

(S)-tert-butyl (1-(3-(1-(quinolin-2-yl)azetidin-3-yl)pyrazin-2-yl)piperidin-3- yl)carbamate

(4-(cyclopropylmethyl)-1-(3-(1-(quinolin-2-yl)azetidin-3-yl)pyrazin-2-yl)piperidin- 4-yl)methanol

2-(3-(3-((1R,5S)-8-methyl-3,8- diazabicyclo[3.2.1]octan-3-yl)pyrazin-2-yl)azetidin-1-yl)quinoline

1-(3-(1-(quinolin-2-yl)azetidin-3- yl)pyrazin-2-yl)pyrrolidin-3-amine

(R- & S-)-methyl (1-(3-(1-(quinolin-2-yl)azetidin-3-yl)pyrazin-2-yl)pyrrolidin-3- yl)carbamate

(R- & S-)-N-(1-(3-(1-(quinolin-2-yl)azetidin-3-yl)pyrazin-2-yl)pyrrolidin-3- yl)methanesulfonamide

(R- & S-)-ethyl (1-(3-(1-(quinolin-2-yl)azetidin-3-yl)pyrazin-2-yl)pyrrolidin-3- yl)carbamate

(R- & S-)-2-methoxy-N-(1-(3-(1-(quinolin-2-yl)azetidin-3-yl)pyrazin-2-yl)pyrrolidin- 3-yl)acetamide

2-(3-(3-(1,4-Diazepan-1-yl)pyrazin-2- yl)azetidin-1-yl)quinoline

Methyl 4-(3-(1-(quinolin-2-yl)azetidin-3-yl)pyrazin-2-yl)-1,4-diazepane-1- carboxylate

methyl methyl(1-(3-(1-quinolin-2-yl)azetidin-3-yl)pyrazin-2-yl)pyrrolidin-3- yl)carbamate

N-methyl-N-(1-(3-(1-(quinolin-2-yl)azetidin-3-yl)pyrazin-2-yl)pyrrolidin-3- yl)methanesulfonamide

Ethyl methyl(1-(3-(1-(quinolin-2-yl)azetidin-3-yl)pyrazin-2-yl)pyrrolidin-3- yl)carbamate

2-(3-(3-(4-chlorophenyl)pyrazin-2- yl)azetidin-1-yl)quinazoline

2-(3-(3-(3-chlorophenyl)pyrazin-2- yl)azetidin-1-yl)quinazoline

2-(3-(3-(2-chlorophenyl)pyrazin-2- yl)azetidin-1-yl)quinazoline

2-(3-(3-(o-tolyl)pyrazin-2-yl)azetidin-1- yl)quinazoline

1-(4-(3-(1-(quinazolin-2-yl)azetidin-3- yl)pyrazin-2-yl)phenyl)ethanone

1-(3-(3-(1-(quinazolin-2-yl)azetidin-3- yl)pyrazin-2-yl)phenyl)ethanone

N-(3-(3-(1-(quinazolin-2-yl)azetidin-3- yl)pyrazin-2-yl)phenyl)acetamide

N-(4-(3-(1-(quinazolin-2-yl)azetidin-3- yl)pyrazin-2-yl)phenyl)methanesulfonamide

N-(3-(3-(1-(quinazolin-2-yl)azetidin-3- yl)pyrazin-2-yl)phenyl)methanesulfonamide

2-(3-(3-(1H-indol-6-yl)pyrazin-2- yl)azetidin-1-yl)quinazoline

2-(3-(3-(1-methyl-1H-indol-5-yl)pyrazin- 2-yl)azetidin-1-yl)quinazoline

2-(3-(3-(1-methyl-1H-indol-6-yl)pyrazin- 2-yl)azetidin-1-yl)quinazoline

5-(3-(1-(quinazolin-2-yl)azetidin-3- yl)pyrazin-2-yl)indolin-2-one

1-methyl-5-(3-(1-(quinazolin-2-yl)azetidin-3-yl)pyrazin-2-yl)indolin-2-one

1-methyl-6-(3-(1-(quinazolin-2- yl)azetidin-3-yl)pyrazin-2-yl)-1H-benzo[d]imidazol-2(3H)-one

2-fluoro-4-(3-(1-(quinazolin-2-yl)azetidin- 3-yl)pyrazin-2-yl)aniline

2-(3-(3-(p-tolyl)pyrazin-2-yl)azetidin-1- yl)quinazoline

2-methyl-6-(3-(1-(quinazolin-2-yl)azetidin-3-yl)pyrazin-2-yl)isoquinolin- 1(2H)-one

2-(3-(3-(1H-indazol-5-yl)pyrazin-2- yl)azetidin-1-yl)quinazoline

5-(3-(1-(quinazolin-2-yl)azetidin-3- yl)pyrazin-2-yl)benzo[d]thiazole

(R & S)-(1H-Benzoimidazol-2-yl)-(3-{3-[4-(1-hydroxy-ethyl)-phenyl]-pyrazin-2- yl}-azetidin-1-yl)-methanone

(R & S)-(1H-Benzoimidazol-2-yl)-(3-{3-[3-(1-hydroxy-ethyl)-phenyl]-pyrazin-2- yl}-azetidin-1-yl)-methanone

(R & S)-(1H-Benzoimidazol-2-yl)-(3-{3-[4-(1-hydroxy-ethyl)-piperidin-1-yl]-pyrazin-2-yl}-azetidin-1-yl)-methanone

1-(4-{3-[1-(1H-Benzoimidazole-2- carbonyl)-azetidin-3-yl]-pyrazin-2-yl}-piperidin-1-yl)-ethanone

1-{3-[1-(1H-Benzoimidazole-2-carbonyl)-azetidin-3-yl]-pyrazin-2-yl}-piperidin-4- one

(1H-Benzoimidazol-2-yl)-{3-[3-(4,4-difluoro-piperidin-1-yl)-pyrazin-2-yl]- azetidin-1-yl}-methanone

(1H-Benzoimidazol-2-yl)-{3-[3-(4-hydroxy-4-methyl-piperidin-1-yl)-pyrazin- 2-yl]-azetidin-1-yl}-methanone

(1H-Benzoimidazol-2-yl)-[3-(5-phenyl-pyrimidin-4-yl)-azetidin-1-yl]-methanone

2-(3-(3-(prop-1-yn-1-yl)pyrazin-2- yl)azetidin-1-yl)quinoline

2-[3-(3-m-Tolyl-pyrazin-2-yl)-azetidin-1- yl]-quinoline

2-[3-(3-m-Tolyl-pyrazin-2-yl)-azetidin-1- yl]-quinazoline

2-[3-(3-m-Tolyl-pyrazin-2-yl)-azetidin-1- yl]-quinoxaline

2-[3-(3-m-Tolyl-pyrazin-2-yl)-azetidin-1- yl]-benzothiazole

2-{3-[3-(3-Methoxy-phenyl)-pyrazin-2- yl]-azetidin-1-yl}-quinoline

2-{3-[3-(3-Methoxy-phenyl)-pyrazin-2- yl]-azetidin-1-yl}-quinazoline

2-{3-[3-(3-Methoxy-phenyl)-pyridin-2-yl]- azetidin-1-yl}-quinoline

2-[3-(3-m-Tolyl-pyridin-2-yl)-azetidin-1- yl]-quinoline

(R & S)-2-{3-[3-(3-Methyl-pyrrolidin-1-yl)-pyridin-2-yl]-azetidin-1-yl}-quinoline

4-Methyl-2′-(1-quinolin-2-yl-azetidin-3-yl)-3,4,5,6-tetrahydro-2H-[1,3′]bipyridinyl

{1-[3-(1-Quinolin-2-yl-piperidin-4-yl)-pyrazin-2-yl]-piperidin-4-yl}-methanol

{1-[3-(1-Quinolin-2-yl-azetidin-3-yl)-pyrazin-2-yl]-piperidin-4-yl}-methanol

{1-[3-(1-Quinazolin-2-yl-azetidin-3-yl)-pyrazin-2-yl]-piperidin-4-yl}-methanol

4-[3-(1-Quinolin-2-yl-azetidin-3-yl)- pyrazin-2-yl]-phenylamine

{1-[3-(1-Benzothiazol-2-yl-azetidin-3-yl)-pyrazin-2-yl]-piperidin-4-yl}-methanol

{1-[3-(1-Benzooxazol-2-yl-azetidin-3-yl)-pyrazin-2-yl]-piperidin-4-yl}-methanol

(1-{3-[1-(5-Methyl-pyridin-2-yl)-azetidin-3-yl]-pyrazin-2-yl}-piperidin-4-yl)- methanol

2-(4-benzylpiperidin-1-yl)-3-(1-(quinolin-2-yl)azetidin-3-yl)quinoxaline

[5′-Fluoro-2′-(1-quinolin-2-yl-azetidin-3- yl)-3,4,5,6-tetrahydro-2H-[1,3′]bipyridinyl-4-yl]-methanol

{1-[3-(1-Quinolin-2-yl-azetidin-3-yl)-pyridazin-4-yl]-piperidin-4-yl}-methanol

(R & S)-2-(3-(3-(3-methylpyrrolidin-1-yl)pyrazin-2-yl)azetidin-1-yl)quinoline

(S or R)-2-(3-(3-(3-methylpyrrolidin-1-yl)pyrazin-2-yl)azetidin-1-yl)quinoline

(R or S)-2-(3-(3-(3-methylpyrrolidin-1-yl)pyrazin-2-yl)azetidin-1-yl)quinoline

2-(1-Quinolin-2-yl-azetidin-3-yl)-3-m- tolyl-quinoxaline

4-[3-(1-Quinolin-2-yl-azetidin-3-yl)- quinoxalin-2-yl]-phenylamine

3-[3-(1-Quinolin-2-yl-azetidin-3-yl)- quinoxalin-2-yl]-phenol

2-(3-Methoxy-phenyl)-3-(1-quinolin-2-yl- azetidin-3-yl)-quinoxaline

2-[3-(1-Quinolin-2-yl-azetidin-3-yl)- pyrazin-2-yl]-phenol

3-[3-(1-Quinolin-2-yl-azetidin-3-yl)- pyrazin-2-yl]-phenol

4-[3-(1-Quinolin-2-yl-azetidin-3-yl)- pyrazin-2-yl]-phenol

2-[3-(1-Quinolin-2-yl-azetidin-3-yl)- pyrazin-2-yl]-phenylamine

3-[3-(1-Quinolin-2-yl-azetidin-3-yl)- pyrazin-2-yl]-phenylamine

4-[3-(1-Quinolin-2-yl-azetidin-3-yl)- pyrazin-2-yl]-phenylamine

2-{3-[3-(4-Fluoro-3-methoxy-phenyl)-pyrazin-2-yl]-azetidin-1-yl}-quinoline

2-Fluoro-4-[3-(1-quinolin-2-yl-azetidin-3- yl)-pyrazin-2-yl]-phenylamine

2-[3-(3-Piperidin-1-yl-pyrazin-2-yl)- azetidin-1-yl]-quinoline

2-{3-[3-(4-Methyl-piperidin-1-yl)-pyrazin-2-yl]-azetidin-1-yl}-quinoline

1-[3-(1-Quinolin-2-yl-azetidin-3-yl)-pyrazin-2-yl]-piperidine-4-carboxylic acid amide

1-[3-(1-Quinolin-2-yl-azetidin-3-yl)-pyrazin-2-yl]-piperidine-4-carboxylic acid dimethylamide

1-[3-(1-Quinolin-2-yl-azetidin-3-yl)-pyrazin-2-yl]-piperidine-4-carboxylic acid methylamide

1-[3′-(1-Quinolin-2-yl-azetidin-3-yl)-2,3,5,6-tetrahydro-[1,2′]bipyrazinyl-4-yl]- ethanone

1-[3-(1-Quinolin-2-yl-azetidin-3-yl)- pyrazin-2-yl]-piperidin-4-ol

2-Methoxy-1-{4-[3-(1-quinolin-2-yl-azetidin-3-yl)-pyrazin-2-yl]-piperidin-1- yl}-ethanone

1-{4-[3-(1-Quinolin-2-yl-azetidin-3-yl)-pyrazin-2-yl]-piperidin-1-yl}-ethanone

N-{4-[3-(1-Quinolin-2-yl-azetidin-3-yl)- pyrazin-2-yl]-phenyl}-acetamide

1-(4-(3-(1-(quinolin-2-yl)azetidin-3-yl)pyrazin-2-yl)-5,6-dihydropyridin-1(2H)- yl)ethanone

(R & S)-1-{1-[3-(1-Quinolin-2-yl-azetidin-3-yl)-pyrazin-2-yl]-piperidin-4-yl}-ethanol

(R or S, absolute stereospecificity notdetermined)-1-{1-[3-(1-Quinolin-2-yl-azetidin-3-yl)-pyrazin-2-yl]-piperidin-4- yl}-ethanol

2-fluoro-5-(3-(1-(quinolin-2-yl)azetidin-3- yl)pyrazin-2-yl)phenol

(1-{3-[1-(6-Methyl-quinolin-2-yl)-azetidin-3-yl]-pyrazin-2-yl}-piperidin-4- yl)-methanol

(1-{3-[1-(7-Fluoro-quinolin-2-yl)-azetidin-3-yl]-pyrazin-2-yl}-piperidin-4-yl)- methanol

(1-{3-[1-(6-Fluoro-quinolin-2-yl)-azetidin-3-yl]-pyrazin-2-yl}-piperidin-4-yl)- methanol

{1-[3-(1-[1,8]Naphthyridin-2-yl-azetidin-3-yl)-pyrazin-2-yl]-piperidin-4-yl}- methanol

(1-{3-[1-(6-Chloro-quinolin-2-yl)-azetidin-3-yl]-pyrazin-2-yl}-piperidin-4-yl)- methanol

(1-{3-[1-(6-Chloro-quinoxalin-2-yl)-azetidin-3-yl]-pyrazin-2-yl}-piperidin-4- yl)-methanol

(1-{3-[1-(6-Methyl-pyridin-2-yl)-azetidin-3-yl]-pyrazin-2-yl}-piperidin-4-yl)- methanol

(1-{3-[1-(5-Chloro-pyridin-2-yl)-azetidin-3-yl]-pyrazin-2-yl}-piperidin-4-yl)- methanol

(1-(3-(1-(5-bromopyridin-2-yl)azetidin-3-yl)pyrazin-2-yl)piperidin-4-yl)methanol

(1-(3-(1-(8-methylquinolin-2-yl)azetidin-3-yl)pyrazin-2-yl)piperidin-4-yl)methanol

(1-{3-[1-(8-Fluoro-quinolin-2-yl)-azetidin-3-yl]-pyrazin-2-yl}-piperidin-4-yl)- methanol

(1-(3-(1-(8-chloroquinolin-2-yl)azetidin-3-yl)pyrazin-2-yl)piperidin-4-yl)methanol

(1-{3-[1-(8-Chloro-quinazolin-2-yl)-azetidin-3-yl]-pyrazin-2-yl}-piperidin-4- yl)-methanol

(1-{3-[1-(7-Chloro-quinazolin-2-yl)-azetidin-3-yl]-pyrazin-2-yl}-piperidin-4- yl)-methanol

(1-{3-[1-(6-Chloro-quinazolin-2-yl)-azetidin-3-yl]-pyrazin-2-yl}-piperidin-4- yl)-methanol

(1-{3-[1-(5-Chloro-quinazolin-2-yl)-azetidin-3-yl]-pyrazin-2-yl}-piperidin-4- yl)-methanol

(1-{3-[1-(7-Chloro-quinoxalin-2-yl)-azetidin-3-yl]-pyrazin-2-yl}-piperidin-4- yl)-methanol

2-[3-(3-Piperidin-1-yl-pyrazin-2-yl)- azetidin-1-yl]-benzothiazole

2-(3-(3-(3-methoxyphenyl)pyrazin-2- yl)azetidin-1-yl)-8-methylquinoline

6-Chloro-2-{3-[3-(3-methoxy-phenyl)-pyrazin-2-yl]-azetidin-1-yl}-quinazoline

8-Chloro-2-{3-[3-(3-methoxy-phenyl)-pyrazin-2-yl]-azetidin-1-yl}-quinoline

7-Fluoro-2-{3-[3-(3-methoxy-phenyl)-pyrazin-2-yl]-azetidin-1-yl}-quinoline

2-{3-[3-(3-Methoxy-phenyl)-pyrazin-2-yl]-azetidin-1-yl}-6-methyl-quinoline

2-{3-[3-(3-Methoxy-phenyl)-pyrazin-2-yl]-azetidin-1-yl}-[1,8]naphthyridine

8-Chloro-2-{3-[3-(3-methoxy-phenyl)-pyrazin-2-yl]-azetidin-1-yl}-quinazoline

5-Chloro-2-{3-[3-(3-methoxy-phenyl)-pyrazin-2-yl]-azetidin-1-yl}-quinazoline

2-(3-(3-(3-methoxyphenyl)pyrazin-2- yl)azetidin-1-yl)-4-phenylpyrimidine

2-(3-(3-(3-methoxyphenyl)pyrazin-2- yl)azetidin-1-yl)benzo[d]thiazole

6-methoxy-2-(3-(3-(3- methoxyphenyl)pyrazin-2-yl)azetidin-1-yl)benzo[d]thiazole

2-(3-(3-(3-methoxyphenyl)pyrazin-2- yl)azetidin-1-yl)-1,6-naphthyridine

6-chloro-2-(3-(3-(3- methoxyphenyl)pyrazin-2-yl)azetidin-1- yl)quinoline

6-fluoro-2-(3-(3-(3- methoxyphenyl)pyrazin-2-yl)azetidin-1-yl)benzo[d]thiazole

2-(3-(3-(3-methoxyphenyl)pyrazin-2-yl)azetidin-1-yl)quinoline-3-carbonitrile

1-[3-(3-Phenyl-pyrazin-2-yl)-azetidin-1- yl]-phthalazine

6-chloro-2-(3-(3-phenylpyrazin-2- yl)azetidin-1-yl)-1H-benzo[d]imidazole

2-(3-(3-phenylpyrazin-2-yl)azetidin-1-yl)- 1H-benzo[d]imidazole

2-((3-(3-phenylpyrazin-2-yl)azetidin-1- yl)methyl)-1H-benzo[d]imidazole

3-(3-(1-(quinolin-2-yl)azetidin-3- yl)pyrazin-2-yl)benzamide

4-(3-(1-(quinolin-2-yl)azetidin-3- yl)pyrazin-2-yl)benzamide

2-fluoro-5-(3-(1-(quinolin-2-yl)azetidin-3- yl)pyrazin-2-yl)benzamide

2-fluoro-4-(3-(1-(quinolin-2-yl)azetidin-3- yl)pyrazin-2-yl)benzamide

2-(3-(3-(1-(quinolin-2-yl)azetidin-3- yl)pyrazin-2-yl)phenyl)propan-2-ol

2-(4-(3-(1-(quinolin-2-yl)azetidin-3- yl)pyrazin-2-yl)phenyl)propan-2-ol

2-(3-(3-(1,2,3,6-tetrahydropyridin-4-yl)pyrazin-2-yl)azetidin-1-yl)quinoline

lithium 3-(3-(1-(quinolin-2-yl)azetidin-3- yl)pyrazin-2-yl)benzoate

(S or R)-2-(3-(3-(3-(pyridin-3-yl)pyrrolidin-1-yl)pyrazin-2-yl)azetidin-1- yl)quinoline

(R or S)-2-(3-(3-(3-(pyridin-3-yl)pyrrolidin-1-yl)pyrazin-2-yl)azetidin-1- yl)quinoline

(1H-Benzoimidazol-2-yl)-{3-[3-(2-methoxy-phenoxy)-pyrazin-2-yl]-azetidin- 1-yl}-methanone

(1H-Benzoimidazol-2-yl)-{3-[3-(3-methoxy-phenoxy)-pyrazin-2-yl]-azetidin- 1-yl}-methanone

(1H-benzoimidazol-2-yl)-{3-[3-(4-methoxy-phenoxy)-pyrazin-2-yl]-azetidin- 1-yl}-methanone

(1H-Benzoimidazol-2-yl)-[3-(3-phenoxy-pyrazin-2-yl)-azetidin-1-yl]-methanone

(1H-benzoimidazol-2-yl)-{3-[3- (tetrahydro-pyran-4-yl)-pyrazin-2-yl]-azetidin-1-yl}-methanone

(7-Chloro-1H-benzoimidazol-2-yl)-[3-(3-phenyl-pyrazin-2-yl)-azetidin-1-yl]- methanone

(6-Chloro-1H-benzoimidazol-2-yl)-[3-(3-phenyl-pyrazin-2-yl)-azetidin-1-yl]- methanone

(7-F luoro-1H-benzoimidazol-2-yl)-[3-(3-phenyl-pyrazin-2-yl)-azetidin-1-yl]- methanone

(6-F luoro-1H-benzoimidazol-2-yl)-[3-(3-phenyl-pyrazin-2-yl)-azetidin-1-yl]- methanone

(6-methyl-1H-benzoimidazol-2-yl)-[3-(3-phenyl-pyrazin-2-yl)-azetidin-1-yl]- methanone

(6-methyl-1H-benzoimidazol-2-yl)-[3-(3-phenyl-pyrazin-2-yl)-azetidin-1-yl]- methanone

(1H-benzoimidazol-2-yl)-{3-[3-(2-methoxy-phenyl)-pyrazin-2-yl]-azetidin-1- yl}-methanone

(1H-benzoimidazol-2-yl)-{3-[3-(3-methoxy-phenyl)-pyrazin-2-yl]-azetidin-1- yl}-methanone

(1H-Benzoimidazol-2-yl)-{3-[3-(4-methoxy-phenyl)-pyrazin-2-yl]-azetidin-1- yl}-methanone

(1H-benzoimidazol-2-yl)-[3-(2-phenyl-pyridin-3-yl)-azetidin-1-yl]-methanone

2-(3-(3-(1H-indol-5-yl)pyrazin-2- yl)azetidin-1-yl)quinazoline

Another aspect of the invention relates to the compounds of Examples36.1 to 36.190 as listed in Table 36 below, or a pharmaceuticallyacceptable salt thereof.

Yet another aspect of the current invention relates to any compound ofthe present invention, or a pharmaceutically-acceptable salt thereof,radiolabeled with a positron emitting radionuclide selected from ¹¹C,¹⁸F, ¹⁵O, ¹³N, ⁷⁶Br, ⁷⁷Br, ¹²³I, or ¹²⁵I.

Yet another aspect of the current invention relates to aradiopharmaceutical composition comprising any compound of the presentinvention, or a pharmaceutically-acceptable salt thereof, radiolabeledwith a positron emitting radionuclide selected from ¹¹C, ¹⁸F, ¹⁵O, ¹³N,⁷⁶Br, ⁷⁷Br, ¹²³I, or ¹²⁵I, and at least one pharmaceutically acceptablecarrier or excipient.

Yet another aspect of the current invention relates to a method for thediagnostic imaging of PDE10 receptors in a mammal, including human, ortissues bearing PDE10 receptors in a mammal, including human brain,which comprises administering to a mammal in need of such diagnosticimaging an effective amount of any compound of the present invention, ora pharmaceutically-acceptable salt thereof, radiolabeled with a positronemitting radionuclide selected from ¹¹C, ¹⁸F, ¹⁵O, ¹³N, ⁷⁶Br, ⁷⁷Br,¹²³I, or ¹²⁵I.

Yet another aspect of the current invention relates to a method for thediagnostic imaging of PDE10 receptors in a mammal, including human, ortissues bearing PDE10 receptors in a mammal, including human brain,which comprises administering to a mammal in need of such diagnosticimaging an effective amount of any compound of the present invention, ora pharmaceutically-acceptable salt thereof, radiolabeled with a positronemitting radionuclide selected from ¹¹C, ¹⁸F, ¹⁵O, ¹³N, ⁷⁶Br, ⁷⁷Br,¹²³I, or ¹²⁵I.

Yet another aspect of the current invention relates to a method for thedetection or quantification of PDE10 receptors in mammalian tissue,including human tissue, which comprises contacting such mammalian tissuein which such detection or quantification is desired with an effectiveamount of any compound of the present invention, or apharmaceutically-acceptable salt thereof, radiolabeled with a positronemitting radionuclide selected from ¹¹C, ¹⁸F, ¹⁵O, ¹³N, ⁷⁶Br, ⁷⁷Br,¹²³I, or ¹²⁵I.

The compounds of this invention may have in general several asymmetriccenters and are typically depicted in the form of racemic mixtures. Thisinvention is intended to encompass racemic mixtures, other racemicmixtures and separate enantiomers and diasteromers.

The present invention includes all pharmaceutically acceptableisotopically-labelled compounds of the present invention wherein one ormore atoms are replaced by atoms having the same atomic number, but anatomic mass or mass number different from the atomic mass or mass numberwhich predominates in nature.

Examples of isotopes suitable for inclusion in the compounds of theinvention include, but are not limited to, isotopes of hydrogen, such as²H and ³H, carbon, such as ¹¹C, ¹³C and ¹⁴C, chlorine, such as ³⁸Cl,fluorine, such as ¹⁸F, iodine, such as ¹²³I and ¹²⁵I, nitrogen, such as¹³N and ¹⁵N, oxygen, such as ¹⁵O, ¹⁷O and ¹⁸O, phosphorus, such as ³²P,and sulphur, such as ³⁵S.

Certain isotopically-labelled compounds of the present invention, forexample, those incorporating a radioactive isotope, are useful in drugand/or substrate tissue distribution studies. The radioactive isotopestritium, i.e. ³H, and carbon-14, i.e. ¹⁴C, are particularly useful forthis purpose in view of their ease of incorporation and ready means ofdetection.

Substitution with heavier isotopes such as deuterium, i.e. ²H, mayafford certain therapeutic advantages resulting from greater metabolicstability, for example, increased in vivo half-life or reduced dosagerequirements, and hence may be preferred in some circumstances.

Substitution with positron emitting isotopes, such as ¹¹C, ¹⁸F, ¹⁵O and¹³N, can be useful in Positron Emission Topography (PET) studies forexamining substrate receptor occupancy.

Isotopically-labeled compounds of the present invention can generally beprepared by conventional techniques known to those skilled in the art orby processes analogous to those described in the accompanying Examplesand Preparations using an appropriate isotopically-labeled reagent inplace of the non-labeled reagent previously employed.

Pharmaceutically acceptable solvates in accordance with the inventioninclude those wherein the solvent of crystallization may be isotopicallysubstituted, e.g. D₂O, d₆-acetone, d₆-DMSO.

Specific embodiments of the present invention include the compoundsexemplified in the Examples below and their pharmaceutically acceptablesalts, complexes, solvates, polymorphs, stereoisomers, metabolites,prodrugs, and other derivatives thereof, Unless otherwise specified, thefollowing definitions apply to terms found in the specification and

The term “C_(α-β)alk” means an alkyl group comprising a minimum of α anda maximum of β carbon atoms in a branched, cyclical or linearrelationship or any combination of the three, wherein α and β representintegers. The alkyl groups described in this section may also containone or two double or triple bonds. A designation of C₀alk indicates adirect bond. Examples of C₁₋₆alkyl include, but are not limited to thefollowing:

The term “benzo group”, alone or in combination, means the divalentradical C₄H₄═, one representation of which is —CH═CH—CH═CH—, that whenvicinally attached to another ring forms a benzene-like ring—for exampletetrahydronaphthylene, indole and the like.

The terms “oxo” and “thioxo” represent the groups ═O (as in carbonyl)and ═S (as in thiocarbonyl), respectively.

The term “halo” or “halogen” means a halogen atoms selected from F, Cl,Br or I.

The term “C_(α-β)haloalk” means an alk group, as described above,wherein one or more hydrogen atom of the alk group is replaced by F, Cl,Br or I.

The term “carbon-linked” means a substituent is linked to another groupthrough a carbon atom. Examples of “carbon-linked” substituents include,but are not limited to the following:

The term “nitrogen-linked” means a substituent is linked to anothergroup through a nitrogen atom. Examples of “nitrogen-linked”substituents include, but are not limited to the following:

The group N(R^(a))R^(a) and the like include substituents where the twoR^(a) groups together form a ring, optionally including a N, O or Satom, and include groups such as:

The group N(C_(α-β)alk) C_(α-β)alk, wherein α and β are as definedabove, include substituents where the two C_(α-β)alk groups togetherform a ring, optionally including a N, O or S atom, and include groupssuch as:

The term “carbocyclyl” means a ring comprising by itself or incombination with other terms, represents, unless otherwise stated,cyclic version of “C_(α-β)alk”. Thus, the term “carbocyclyl” is meant tobe included in the terms “C_(α-β)alk”. Examples of carbocycle includecyclopentyl, cyclohexyl, or partially unsaturated ring such as1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl, cyclobutylene,cyclohexylene and the like. Unless otherwise stated, carbocycle caninclude fully saturated ring such as phenyl or naphthyl.

The term “heteroatom” means N, O and S.

The term “heterocyclyl” means a ring comprising at least one carbon atomand at least one other atom selected from N, O and S. “Heterocyclyl”includes aromatic heterocyclic ring which is commonly known asheteroaryl. Thus, the term “heteroaryl” is meant to be included in theterms “heterocyclyl”. Examples of heterocycles that may be found in theclaims include, but are not limited to, the following:

The term “pharmaceutically acceptable salt” means a salt prepared byconventional means, and are well known by those skilled in the art. The“pharmacologically acceptable salts” include basic salts of inorganicand organic acids, including but not limited to hydrochloric acid,hydrobromic acid, sulfuric acid, phosphoric acid, methanesulfonic acid,ethanesulfonic acid, malic acid, acetic acid, oxalic acid, tartaricacid, citric acid, lactic acid, fumaric acid, succinic acid, maleicacid, salicylic acid, benzoic acid, phenylacetic acid, mandelic acid andthe like. When compounds of the invention include an acidic functionsuch as a carboxy group, then suitable pharmaceutically acceptablecation pairs for the carboxy group are well known to those skilled inthe art and include alkaline, alkaline earth, ammonium, quaternaryammonium cations and the like. For additional examples of“pharmacologically acceptable salts,” and Berge et al., J. Pharm. Sci.66:1 (1977).

The term “saturated, partially-saturated or unsaturated” includessubstituents saturated with hydrogens, substituents completelyunsaturated with hydrogens and substituents partially saturated withhydrogens.

Representative examples of “saturated, partially-saturated orunsaturated” five to eight membered rings, optionally having one tothree heteroatoms, are cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyland phenyl. Further exemplary five membered rings are furyl, thienyl,pyrrolyl, 2-pyrrolinyl, 3-pyrrolinyl, pyrrolidinyl, 1,3-dioxolanyl,oxazolyl, thiazolyl, imidazolyl, 2H-imidazolyl, 2-imidazolinyl,imidazolidinyl, pyrazolyl, 2-pyrazolinyl, pyrazolidinyl, isoxazolyl,isothiazolyl, 1,2-dithiolyl, 1,3-dithiolyl, 3H-1,2-oxathiolyl,1,2,3-oxadizaolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl,1,3,4oxadiazolyl, 1,2,3-triazolyl, 1,2,4-trizaolyl, 1,3,4-thiadiazolyl,3H-1,2,3-dioxazolyl, 1,2,4-dioxazolyl, 1,3,2-dioxazolyl,1,3,4-dioxazolyl, 5H-1,2,5-oxathiazolyl, and 1,3-oxathiolyl.

Further exemplary six membered rings are 2H-pyranyl, 4H-pyranyl,pyridinyl, piperidinyl, 1,2-dioxinyl, 1,3-dioxinyl, 1,4-dioxanyl,morpholinyl, 1,4-dithianyl, thiomorpholinyl, pyndazinyl, pyrimidinyl,pyrazinyl, piperazinyl, 1,3,5-triazinyl, 1,2,4-triazinyl,1,2,3-triazinyl, 1,3,5-trithianyl, 4H-1,2-oxazinyl, 2H-1,3-oxazinyl,6H-1,3-oxazinyl, 6H-1,2-oxazinyl, 1,4-oxazinyl, 2H-1,2-oxazinyl,4H-1,4-oxazinyl, 1,2,5-oxathiazinyl, 1,4-oxazinyl, o-isoxazinyl,p-isoxazinyl, 1,2,5-oxathiazinyl, 1,2,6-(3 oxathiazinyl, and1,4,2-oxadiazinyl.

Further exemplary seven membered rings are azepinyl, oxepinyl, thiepinyland 1,2,4-triazepinyl.

Further exemplary eight membered rings are cyclooctyl, cyclooctenyl andcyclooctadienyl.

The term “monocyclic” means a group having a single saturated,partially-saturated, or unsaturated ring system. Typically a monocyclicring system can have from 3- to 8 atoms in the ring system. The termincludes, but is not limited to, cyclopropyl, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl, phenyl, and the like.

The term “bicyclic” means a group having two interconnected saturated,partially-saturated, or unsaturated rings that include stable bridged,fused, or spiro rings. The bicyclic ring may be attached at any carbonor heteroatom which affords a stable group. Typically a bicyclic ringsystem can have from 6- to 14 atoms in the ring system. The termincludes, but is not limited to, benzimidazole, naphthyl,bicyclo[3.1.0]hexane, bicyclo[4.1.0]heptane, spiro[2.4]heptane,spiro[2.5]octane, bicyclo[4.4.0]decane, bicyclo[4.3.0]nonane,bicyclo[3.3.1]nonane, bicyclo[3.2.1]octane, spiro[4.5]decane,spiro[3.5]nonane, norbornane, bicyclo[2.1.0]pentane,bicyclo[3.3.0]octane, bicyclo[2.2.2]octane, bicyclo[3.3.3]undecane, andthe like.

The term “tricyclic” means a group having three interconnectedsaturated, partially-saturated, or unsaturated rings that include stablebridged, fused, or spiro rings. Typically a tricyclic ring system canhave from 11 to 18 ring atoms in the ring system. The term includes, butis not limited to, adamantyl, tricyclo[5.2.1.0.sup.2,6]decane, and thelike.

Exemplary bicyclic rings consisting of two fused partially saturated,fully saturated or fully unsaturated five and/or six membered rings,optionally having one to four heteroatoms, are indolizinyl, indolyl,isoindolyl, indolinyl, cyclopenta(b)pyridinyl, pyrano(3,4-b)pyrrolyl,benzofuryl, isobenzofuryl, benzo[b]thienyl, benzo[c]thienyl,1H-indazolyl, indoxazinyl, benzoxazolyl, anthranilyl, benzimidazolyl,benzthiazolyl, purinyl, quinolinyl, isoquinolinyl, cinnolinyl,phthalazinyl, quinazolinyl, quinoxalinyl, 1,8-naphthyridinyl,pteridinyl, indenyl, isoindenyl, naphthyl, tetralinyl, decalinyl,2H-1-benzopyranyl, pyrido(3,4-b)pyridinyl, pyrido(3,2-b)pyridinyl,pyrido(4,3-b)-pyridinyl, 2H-1,3-benzoxazinyl, 2H-1,4-benzoxazinyl,1H-2,3-benzoxazinyl, 4H-3,1-benzoxazinyl, 2H-1,2-benzoxazinyl and4H-1,4-benzoxazinyl.

A cyclic ring group may be bonded to another group in more than one way.If no particular bonding arrangement is specified, then all possiblearrangements are intended. For example, the term “pyridyl” includes 2-,3-, or 4-pyridyl, and the term “thienyl” includes 2-, or 3-thienyl.

The term “substituted” means that a hydrogen atom on a molecule or groupis replaced with a group or atom. Typical substitutents include:halogen, C₁₋₈alkyl, hydroxyl, C₁₋₈alkoxy, —NR^(x)R^(x), nitro, cyano,halo or perhaloC₁₋₈alkyl, C₂₋₈alkenyl, C₂₋₈alkynyl, —SR^(x),—S(═O)₂R^(x), —C(═O)OR^(x), —C(═O)R^(x), wherein each R^(x) isindependently hydrogen or C₁-C₈ alkyl. It is noted that when thesubstituent is —NR^(x)R^(x), the R^(x) groups may be joined togetherwith the nitrogen atom to form a ring.

A group or atom that replaces a hydrogen atom is also called asubstituent.

Any particular molecule or group can have one or more substituentdepending on the number of hydrogen atoms that can be replaced.

The symbol “—” represents a covalent bond and can also be used in aradical group to indicate the point of attachment to another group. Inchemical structures, the symbol is commonly used to represent a methylgroup in a molecule.

The term “leaving group” generally refers to groups readily displaceableby a nucleophile, such as an amine, a thiol or an alcohol nucleophile.Such leaving groups are well known in the art. Examples of such leavinggroups include, but are not limited to, N-hydroxysuccinimide,N-hydroxybenzotriazole, halides, triflates, tosylates and the like.Preferred leaving groups are indicated herein where appropriate.

The term “protecting group” generally refers to groups well known in theart which are used to prevent selected reactive groups, such as carboxy,amino, hydroxy, mercapto and the like, from undergoing undesiredreactions, such as nucleophilic, electrophilic, oxidation, reduction andthe like. Preferred protecting groups are indicated herein whereappropriate. Examples of amino protecting groups include, but are notlimited to, aralkyl, substituted aralkyl, cycloalkenylalkyl andsubstituted cycloalkenyl alkyl, allyl, substituted allyl, acyl,alkoxycarbonyl, aralkoxycarbonyl, silyl and the like. Examples ofaralkyl include, but are not limited to, benzyl, ortho-methylbenzyl,trityl and benzhydryl, which can be optionally substituted with halogen,alkyl, alkoxy, hydroxy, nitro, acylamino, acyl and the like, and salts,such as phosphonium and ammonium salts. Examples of aryl groups includephenyl, naphthyl, indanyl, anthracenyl, 9-(9-phenylfluorenyl),phenanthrenyl, durenyl and the like. Examples of cycloalkenylalkyl orsubstituted cycloalkylenylalkyl radicals, preferably have 6-10 carbonatoms, include, but are not limited to, cyclohexenyl methyl and thelike. Suitable acyl, alkoxycarbonyl and aralkoxycarbonyl groups includebenzyloxycarbonyl, t-butoxycarbonyl, iso-butoxycarbonyl, benzoyl,substituted benzoyl, butyryl, acetyl, trifluoroacetyl, trichloro acetyl,phthaloyl and the like. A mixture of protecting groups can be used toprotect the same amino group, such as a primary amino group can beprotected by both an aralkyl group and an aralkoxycarbonyl group. Aminoprotecting groups can also form a heterocyclic ring with the nitrogen towhich they are attached, for example, 1,2-bis(methylene)benzene,phthalimidyl, succinimidyl, maleimidyl and the like and where theseheterocyclic groups can further include adjoining aryl and cycloalkylrings. In addition, the heterocyclic groups can be mono-, di- ortri-substituted, such as nitrophthalimidyl. Amino groups may also beprotected against undesired reactions, such as oxidation, through theformation of an addition salt, such as hydrochloride, toluenesulfonicacid, trifluoroacetic acid and the like. Many of the amino protectinggroups are also suitable for protecting carboxy, hydroxy and mercaptogroups. For example, aralkyl groups. Alkyl groups are also suitablegroups for protecting hydroxy and mercapto groups, such as tert-butyl.

The term “silyl protecting groups” means silicon atoms optionallysubstituted by one or more alkyl, aryl and aralkyl groups. Suitablesilyl protecting groups include, but are not limited to, trimethylsilyl,triethylsilyl, triisopropylsilyl, tert-butyldimethylsilyl,dimethylphenylsilyl, 1,2-bis(dimethylsilyl)benzene,1,2-bis(dimethylsilyl)ethane and diphenylmethylsilyl. Silylation of anamino groups provide mono- or di-silylamino groups. Silylation ofaminoalcohol compounds can lead to a N,N,O-trisilyl derivative. Removalof the silyl function from a silyl ether function is readilyaccomplished by treatment with, for example, a metal hydroxide orammonium fluoride reagent, either as a discrete reaction step or in situduring a reaction with the alcohol group. Suitable silylating agentsare, for example, trimethylsilyl chloride, tert-butyl-dimethylsilylchloride, phenyldimethylsilyl chloride, diphenylmethyl silyl chloride ortheir combination products with imidazole or DMF. Methods for silylationof amines and removal of silyl protecting groups are well known to thoseskilled in the art. Methods of preparation of these amine derivativesfrom corresponding amino acids, amino acid amides or amino acid estersare also well known to those skilled in the art of organic chemistryincluding amino acid/amino acid ester or aminoalcohol chemistry.

Protecting groups are removed under conditions which will not affect theremaining portion of the molecule. These methods are well known in theart and include acid hydrolysis, hydrogenolysis and the like. Apreferred method involves removal of a protecting group, such as removalof a benzyloxycarbonyl group by hydrogenolysis utilizing palladium oncarbon in a suitable solvent system such as an alcohol, acetic acid, andthe like or mixtures thereof. A t-butoxycarbonyl protecting group can beremoved utilizing an inorganic or organic acid, such as HCl ortrifluoroacetic acid, in a suitable solvent system, such as dioxane ormethylene chloride. The resulting amino salt can readily be neutralizedto yield the free amine. Carboxy protecting group, such as methyl,ethyl, benzyl, tert-butyl, 4-methoxyphenylmethyl and the like, can beremoved under hydrolysis and hydrogenolysis conditions well known tothose skilled in the art.

It should be noted that compounds of the invention may contain groupsthat may exist in tautomeric forms, such as cyclic and acyclic amidineand guanidine groups, heteroatom substituted aromatic heterocyclylgroups (Y′═O, S, NR), and the like, which are illustrated in thefollowing examples:

and though one form is named, described, displayed and/or claimedherein, all the tautomeric forms are intended to be inherently includedin such name, description, display and/or claim.

Prodrugs of the compounds of this invention are also contemplated bythis invention. A prodrug is an active or inactive compound that ismodified chemically through in vivo physiological action, such ashydrolysis, metabolism and the like, into a compound of this inventionfollowing administration of the prodrug to a patient. The suitabilityand techniques involved in making and using prodrugs are well known bythose skilled in the art. For a general discussion of prodrugs involvingesters see Svensson and Tunek Drug Metabolism Reviews 165 (1988) andBundgaard Design of Prodrugs, Elsevier (1985). Examples of a maskedcarboxylate anion include a variety of esters, such as alkyl (forexample, methyl, ethyl), cycloalkyl (for example, cyclohexyl), aralkyl(for example, benzyl, p-methoxybenzyl), and alkylcarbonyloxyalkyl (forexample, pivaloyloxymethyl). Amines have been masked asarylcarbonyloxymethyl substituted derivatives which are cleaved byesterases in vivo releasing the free drug and formaldehyde (Bungaard J.Med. Chem. 2503 (1989)). Also, drugs containing an acidic NH group, suchas imidazole, imide, indole and the like, have been masked withN-acyloxymethyl groups (Bundgaard Design of Prodrugs, Elsevier (1985)).Hydroxy groups have been masked as esters and ethers. EP 039,051 (Sloanand Little, Apr. 11, 1981) discloses Mannich-base hydroxamic acidprodrugs, their preparation and use.

The term “therapeutically effective amount” means an amount of acompound that ameliorates, attenuates or eliminates one or more symptomof a particular disease or condition, or prevents or delays the onset ofone of more symptom of a particular disease or condition.

The term “patient” means animals, such as dogs, cats, cows, horses,sheep and humans. Particular patients are mammals. The term patientincludes males and females.

The term “pharmaceutically acceptable” means that the referencedsubstance, such as a compound of Formula I, or a salt of a compound ofFormula I, or a formulation containing a compound of Formula I, or aparticular excipient, are suitable for administration to a patient.

The terms “treating”, “treat” or “treatment” and the like includepreventative (e.g., prophylactic) and palliative treatment.

The term “excipient” means any pharmaceutically acceptable additive,carrier, diluent, adjuvant, or other ingredient, other than the activepharmaceutical ingredient (API), which is typically included forformulation and/or administration to a patient.

Utility and Methods of Use

Provided herein are methods for treating a disorder or disease byinhibiting PDE10 enzyme. The methods, in general, comprises the step ofadministering a therapeutically effective amount of a compounds of thepresent invention, or an individual stereoisomer, a mixture ofstereoisomers, or a pharmaceutically acceptable salt or solvate thereof,to a patient in need thereof to treat the disorder or disease.

In certain embodiments, this invention provides a use of a compound asdescribed herein in the manufacture of a medicament for treating adisorder or disease treatable by inhibition of PDE10.

The compounds of the present invention inhibit PDE10 enzyme activity,and hence raise the levels of cAMP or cGMP within cells that expressPDE10. Accordingly, inhibition of PDE10 enzyme activity would be usefulin the treatment of diseases caused by deficient amounts of cAMP or cGMPin cells. PDE10 inhibitors would also be of benefit in cases whereinraising the amount of cAMP or cGMP above normal levels results in atherapeutic effect. Inhibitors of PDE10 may be used to treat disordersof the peripheral and central nervous system, cardiovascular diseases,cancer, gastro-enterological diseases, endocrinological diseases andurological diseases.

Indications that may be treated with PDE10 inhibitors, either alone orin combination with other drugs, include, but are not limited to, thosediseases thought to be mediated in part by the basal ganglia, prefrontalcortex, and hippocampus. These indications include psychoses,Parkinson's disease, dementias, obsessive compulsive disorder, tardivedyskinesia, choreas, depression, mood disorders, impulsivity, drugaddiction, attention deficit/hyperactivity disorder (ADHD), depressionwith parkinsonian states, personality changes with caudate or putamendisease, dementia and mania with caudate and pallidal diseases, andcompulsions with pallidal disease.

Psychoses are disorders that affect an individual's perception ofreality. Psychoses are characterized by delusions and hallucinations.The compounds of the present invention are suitable for use in treatingpatients suffering from all forms of psychoses, including, but notlimited to, schizophrenia, late-onset schizophrenia, schizoaffectivedisorders, prodromal schizophrenia, and bipolar disorders. Treatment canbe for the positive symptoms of schizophrenia as well as for thecognitive deficits and negative symptoms. Other indications for PDE10inhibitors include psychoses resulting from drug abuse (includingamphetamines and PCP), encephalitis, alcoholism, epilepsy, Lupus,sarcoidosis, brain tumors, multiple sclerosis, dementia with Lewybodies, or hypoglycemia. Other psychiatric disorders, like posttraumaticstress disorder (PTSD), and schizoid personality can also be treatedwith PDE10 inhibitors.

Obsessive-compulsive disorder (OCD) has been linked to deficits in thefrontal-striatal neuronal pathways (Saxena et al., Br. J. PsychiatrySuppl, 35:26-37, 1998). Neurons in these pathways project to striatalneurons that express PDE10. PDE10 inhibitors cause cAMP to be elevatedin these neurons; elevations in cAMP result in an increase in CREBphosphorylation and thereby improve the functional state of theseneurons. The compounds of the present invention are therefore suitablefor use in the indication of OCD. OCD may result, in some cases, fromstreptococcal infections that cause autoimmune reactions in the basalganglia (Giedd et al., Am J Psychiatry. 157:281-283, 2000). BecausePDE10 inhibitors may serve a neuroprotective role, administration ofPDE10 inhibitors may prevent the damage to the basal ganglia afterrepeated streptococcal infections and thereby prevent the development ofOCD.

In the brain, the level of cAMP or cGMP within neurons is believed to berelated to the quality of memory, especially long term memory. Withoutwishing to be bound to any particular mechanism, it is proposed that,since PDE10 degrades cAMP or cGMP, the level of this enzyme affectsmemory in animals, for example, in humans. A compound that inhibits cAMPphosphodiesterase (PDE) can thereby increase intracellular levels ofcAMP, which in turn activate a protein kinase that phosphorylates atranscription factor (cAMP response binding protein). The phosphorylatedtranscription factor then binds to a DNA promoter sequence to activategenes that are important in long term memory. The more active such genesare, the better is long-term memory. Thus, by inhibiting aphosphodiesterase, long term memory can be enhanced.

Dementias are diseases that include memory loss and additionalintellectual impairment separate from memory. The compounds of thepresent invention are suitable for use in treating patients sufferingfrom memory impairment in all forms of dementia. Dementias areclassified according to their cause and include: neurodegenerativedementias (e.g., Alzheimer's, Parkinson's disease, Huntington's disease,Pick's disease), vascular (e.g., infarcts, hemorrhage, cardiacdisorders), mixed vascular and Alzheimer's, bacterial meningitis,Creutzfeld-Jacob Disease, multiple sclerosis, traumatic (e.g., subduralhematoma or traumatic brain injury), infectious (e.g., HIV), genetic(down syndrome), toxic (e.g., heavy metals, alcohol, some medications),metabolic (e.g., vitamin B12 or folate deficiency), CNS hypoxia,Cushing's disease, psychiatric (e.g., depression and schizophrenia), andhydrocephalus.

The condition of memory impairment is manifested by impairment of theability to learn new information and/or the inability to recallpreviously learned information. The present invention includes methodsfor dealing with memory loss separate from dementia, including mildcognitive impairment (MCI) and age-related cognitive decline. Thepresent invention includes methods of treatment for memory impairment asa result of disease. Memory impairment is a primary symptom of dementiaand can also be a symptom associated with such diseases as Alzheimer'sdisease, schizophrenia, Parkinson's disease, Huntington's disease,Pick's disease, Creutzfeld-Jakob disease, HIV, cardiovascular disease,and head trauma as well as age-related cognitive decline. The compoundsof the present invention are suitable for use in the treatment of memoryimpairment due to, for example, Alzheimer's disease, multiple sclerosis,amylolaterosclerosis (ALS), multiple systems atrophy (MSA),schizophrenia, Parkinson's disease, Huntington's disease, Pick'sdisease, Creutzfeld-Jakob disease, depression, aging, head trauma,stroke, spinal cord injury, CNS hypoxia, cerebral senility, diabetesassociated cognitive impairment, memory deficits from early exposure ofanesthetic agents, multiinfarct dementia and other neurologicalconditions including acute neuronal diseases, as well as HIV andcardiovascular diseases.

The compounds of the present invention are also suitable for use in thetreatment of a class of disorders known as polyglutamine-repeatdiseases. These diseases share a common pathogenic mutation. Theexpansion of a CAG repeat, which encodes the amino acid glutamine,within the genome leads to production of a mutant protein having anexpanded polyglutamine region. For example, Huntington's disease hasbeen linked to a mutation of the protein huntingtin. In individuals whodo not have Huntington's disease, huntingtin has a polyglutamine regioncontaining about 8 to 31 glutamine residues. For individuals who haveHuntington's disease, huntingtin has a polyglutamine region with over 37glutamine residues. Aside from Huntington's disease (HD), other knownpolyglutamine-repeat diseases and the associated proteins includedentatorubral-pallidoluysian atrophy, DRPLA (atrophin-1);spinocerebellar ataxia type-1 (ataxin-1); spinocerebellar ataxia type-2(ataxin-2); spinocerebellar ataxia type-3 (also called Machado-Josephdisease or MJD) (ataxin-3); spinocerebellar ataxia type-6 (alpha1a-voltage dependent calcium channel); spinocerebellar ataxia type-7(ataxin-7); and spinal and bulbar muscular atrophy (SBMA, also know asKennedy disease).

The basal ganglia are important for regulating the function of motorneurons; disorders of the basal ganglia result in movement disorders.Most prominent among the movement disorders related to basal gangliafunction is Parkinson's disease (Obeso et al., Neurology. 62(1 Suppl1):517-30, 2004). Other movement disorders related to dysfunction of thebasal ganglia include tardive dyskinesia, progressive supranuclear palsyand cerebral palsy, corticobasal degeneration, multiple system atrophy,Wilson disease, dystonia, tics, and chorea. The compounds of theinvention are also suitable for use to treat movement disorders relatedto dysfunction of basal ganglia neurons.

PDE10 inhibitors are useful in raising cAMP or cGMP levels and preventneurons from undergoing apoptosis. PDE10 inhibitors may beanti-inflammatory by raising cAMP in glial cells. The combination ofanti-apoptotic and anti-inflammatory properties, as well as positiveeffects on synaptic plasticity and neurogenesis, make these compoundsuseful to treat neurodegeneration resulting from any disease or injury,including stroke, spinal cord injury, Alzheimer's disease, multiplesclerosis, amylolaterosclerosis (ALS), and multiple systems atrophy(MSA).

Autoimmune diseases or infectious diseases that affect the basal gangliamay result in disorders of the basal ganglia including ADHD, OCD, tics,Tourette's disease, Sydenham chorea. In addition, any insult to thebrain can potentially damage the basal ganglia including strokes,metabolic abnormalities, liver disease, multiple sclerosis, infections,tumors, drug overdoses or side effects, and head trauma. Accordingly,the compounds of the invention can be used to stop disease progressionor restore damaged circuits in the brain by a combination of effectsincluding increased synaptic plasticity, neurogenesis,anti-inflammatory, nerve cell regeneration and decreased apoptosis.

The growth of some cancer cells is inhibited by cAMP and cGMP. Upontransformation, cells may become cancerous by expressing PDE10 andreducing the amount of cAMP or cGMP within cells. In these types ofcancer cells, inhibition of PDE10 activity inhibits cell growth byraising cAMP. In some cases, PDE10 may be expressed in the transformed,cancerous cell but not in the parent cell line. In transformed renalcarcinoma cells, PDE10 is expressed and PDE10 inhibitors reduce thegrowth rate of the cells in culture. Similarly, breast cancer cells areinhibited by administration of PDE10 inhibitors. Many other types ofcancer cells may also be sensitive to growth arrest by inhibition ofPDE10. Therefore, compounds disclosed in this invention can be used tostop the growth of cancer cells that express PDE10.

The compounds of the invention are also suitable for use in thetreatment of diabetes and related disorders such as obesity, by focusingon regulation of the cAMP signaling system. By inhibiting PDE-10,especially PDE-10A, intracellular levels of cAMP are increased, therebyincreasing the release of insulin-containing secretory granules and,therefore, increasing insulin secretion. See, for example, WO2005/012485. The compounds of Formula (I) can also be used to treatdiseases disclosed in US Patent application publication No. 2006/019975.

Testing

The PDE10 inhibitory activities of the compounds of the presentinvention can be tested, for example, using the in vitro and in vivoassays described in the Biological Examples below.

Administration and Pharmaceutical Compositions

In general, the compounds of this invention can be administered in atherapeutically effective amount by any of the accepted modes ofadministration for agents that serve similar utilities. The actualamount of a compound of this invention, i.e., the active ingredient,depends upon numerous factors, such as the severity of the disease to betreated, the age and relative health of the subject, the potency of thecompound used, the route and form of administration, and other factors.

Therapeutically effective amounts of compounds of formula (I) may rangefrom approximately 0.1-1000 mg per day; preferably 0.5 to 250 mg/day,more preferably 3.5 mg to 70 mg per day.

In general, compounds of this invention can be administered aspharmaceutical compositions by any one of the following routes: oral,systemic (e.g., transdermal, intranasal or by suppository), orparenteral (e.g., intramuscular, intravenous or subcutaneous)administration. The preferred manner of administration is oral using aconvenient daily dosage regimen, which can be adjusted according to thedegree of affliction. Compositions can take the form of tablets, pills,capsules, semisolids, powders, sustained release formulations,solutions, suspensions, elixirs, aerosols, or any other appropriatecompositions.

The choice of formulation depends on various factors, such as the modeof drug administration (e.g., for oral administration, formulations inthe form of tablets, pills or capsules are preferred) and thebioavailability of the drug substance. Recently, pharmaceuticalformulations have been developed especially for drugs that show poorbioavailability based upon the principle that bioavailability can beincreased by increasing the surface area, i.e., decreasing particlesize. For example, U.S. Pat. No. 4,107,288 describes a pharmaceuticalformulation having particles in the size range from 10 to 1,000 nm inwhich the active material is supported on a crosslinked matrix ofmacromolecules. U.S. Pat. No. 5,145,684 describes the production of apharmaceutical formulation in which the drug substance is pulverized tonanoparticles (average particle size of 400 nm) in the presence of asurface modifier and then dispersed in a liquid medium to give apharmaceutical formulation that exhibits remarkably highbioavailability.

The compositions are comprised of, in general, a compounds of thepresent invention in combination with at least one pharmaceuticallyacceptable excipient. Acceptable excipients are non-toxic, aidadministration, and do not adversely affect the therapeutic benefit ofthe compounds of the present invention. Such excipient may be any solid,liquid, semi-solid or, in the case of an aerosol composition, gaseousexcipient that is generally available to one of skill in the art.

Solid pharmaceutical excipients include starch, cellulose, talc,glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silicagel, magnesium stearate, sodium stearate, glycerol monostearate, sodiumchloride, dried skim milk and the like. Liquid and semisolid excipientsmay be selected from glycerol, propylene glycol, water, ethanol andvarious oils, including those of petroleum, animal, vegetable orsynthetic origin, e.g., peanut oil, soybean oil, mineral oil, sesameoil, etc. Preferred liquid carriers, particularly for injectablesolutions, include water, saline, aqueous dextrose, and glycols.

Compressed gases may be used to disperse a compound of this invention inaerosol form. Inert gases suitable for this purpose are nitrogen, carbondioxide, etc.

Other suitable pharmaceutical excipients and their formulations aredescribed in Remington's Pharmaceutical Sciences, Gennaro, A. R. (MackPublishing Company, 18th ed., 1995).

The level of the compound in a formulation can vary within the fullrange employed by those skilled in the art. Typically, the formulationcontains, on a weight percent (wt %) basis, from about 0.01-99.99 wt %of a compounds of the present invention based on the total formulation,with the balance being one or more suitable pharmaceutical excipients.Preferably, the compound is present at a level of about 1-80 wt %.

The compounds can be administered as the sole active agent or incombination with other pharmaceutical agents such as other agents usedin the treatment of psychoses, especially schizophrenia and bipolardisorder, obsessive-compulsive disorder, Parkinson's disease,Alzheimer's disease, cognitive impairment and/or memory loss, e.g.,nicotinic α-7 agonists, PDE4 inhibitors, other PDE10 inhibitors, calciumchannel blockers, muscarinic m1 and m2 modulators, adenosine receptormodulators, ampakines, NMDA-R modulators, mGluR modulators, dopaminemodulators, serotonin modulators, canabinoid modulators, andcholinesterase inhibitors (e.g., donepezil, rivastigimine, andgalanthanamine). In such combinations, each active ingredient can beadministered either in accordance with their usual dosage range or adose below their usual dosage range, and can be administered eithersimultaneously or sequentially.

Drugs suitable in combination with the compounds of the presentinvention include, but are not limited to, other suitable schizophreniadrugs such as Clozaril, Zyprexa, Risperidone, and Seroquel; bipolardisorder drugs, including, but not limited to, Lithium, Zyprexa, andDepakote; Parkinson's disease drugs, including, but not limited to,Levodopa, Parlodel, Permax, Mirapex, Tasmar, Contan, Kemadin, Artane,and Cogentin; agents used in the treatment of Alzheimer's disease,including, but not limited to, Reminyl, Cognex, Aricept, Exelon,Akatinol, Neotropin, Eldepryl, Estrogen and Cliquinol; agents used inthe treatment of dementia, including, but not limited to, Thioridazine,Haloperidol, Risperidone, Cognex, Aricept, and Exelon; agents used inthe treatment of epilepsy, including, but not limited to, Dilantin,Luminol, Tegretol, Depakote, Depakene, Zarontin, Neurontin, Barbita,Solfeton, and Felbatol; agents used in the treatment of multiplesclerosis, including, but not limited to, Detrol, Ditropan XL,OxyContin, Betaseron, Avonex, Azothioprine, Methotrexate, and Copaxone;agents used in the treatment of Huntington's disease, including, but notlimited to, Amitriptyline, Imipramine, Despiramine, Nortriptyline,Paroxetine, Fluoxetine, Setraline, Terabenazine, Haloperidol,Chloropromazine, Thioridazine, Sulpride, Quetiapine, Clozapine, andRisperidone; agents useful in the treatment of diabetes, including, butnot limited to, PPAR ligands (e.g. agonists, antagonists, such asRosiglitazone, Troglitazone and Pioglitazone), insulin secretagogues(e.g., sulfonylurea drugs, such as Glyburide, Glimepiride,Chlorpropamide, Tolbutamide, and Glipizide, and non-sulfonylsecretagogues), α-glucosidase inhibitors (such as Acarbose, Miglitol,and Voglibose), insulin sensitizers (such as the PPAR-γ agonists, e.g.,the glitazones; biguanides, PTP-1B inhibitors, DPP-IV inhibitors, and11beta-HSD inhibitors), hepatic glucose output lowering compounds (suchas glucagon antagonists and metaformin, e.g., Glucophage and GlucophageXR), insulin and insulin derivatives (both long and short acting formsand formulations of insulin); and anti-obesity drugs, including, but notlimited to, β-3 agonists, CB-1 agonists, neuropeptide Y5 inhibitors,Ciliary Neurotrophic Factor and derivatives (e.g., Axokine), appetitesuppressants (e.g., Sibutramine), and lipase inhibitors (e.g.,Orlistat).

EXPERIMENTAL

Unless otherwise noted, all materials were purchased from SinopharmChemical Reagent Co., Ltd and used without further purification. Allmicrowave assisted reactions were conducted with a InitiatorSynthesizer® from Biotage®. All compounds showed NMR spectra consistentwith their assigned structures. Melting points were determined on aBuchi apparatus and are uncorrected. Mass spectral data was determinedby electrospray ionization technique. All examples were purified to >90%purity as determined by high-performance liquid chromatography. Unlessotherwise stated, reactions were run at room temperature.

The following abbreviations are commonly used:

-   Ac the group CH₃—(CO)—-   AcOH or HOAc acetic acid-   Ac₂O acetic anhydride-   BINAP 2,2′-bis(diphenylphosphino)-1,1′-binaphthalene-   BnO Benzyloxy-   Boc₂O di-tert-butyl dicarbonate-   BTEA-Cl benzyltriethylammonium chloride-   Bz Benzyl group-   Cbz carboxylic acid benzyl ester-   CDI 1,1′-carbonyldiimidazole-   d Day-   DCM Dichloromethane-   DIAD (CH₃)₂CHOOCN═NCOOCH(CH₃)₂-   DIEA N,N-diisopropylethylamine-   Diox Dioxane-   DIPEA diisopropylethyl amine-   DMA Dimethylamine-   DMAP 4-(dimethylamino)pyridine-   DME Dimethoxyethane-   DMF N,N-dimethylformamide-   Dess-Martin Periodinane    1,1,1-Tris(acetyloxy)-1,1-dihydro-1,2-benziodoxol-3-(1H)-one-   DMSO dimethyl sulfoxide-   DPPA diphenyl phosphoryl azide-   EDCI N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride-   ESI-MS electrospray ionization mass spectrometry-   Et₂O diethyl ether-   EtOAc ethyl acetate-   EtOH ethyl alcohol-   Et₃N triethyl amine-   g Grams-   h hour or hours-   HATU O-(7-Azobenzotriazol-1-yl)-1,1,3,3-tetramethyluronium    hexafluorophosphate-   HBTU 2-(1H-Benzotriazole-1-yl)-1,1,3,3-tetramethylaminium    hexafluorophosphate-   HCl Hydrochloric acid-   HPLC high pressure liquid chromatography-   IPA isopropyl alcohol-   iPr₂NEt diisopropylethylamine-   iPrOH Isopropyl alcohol-   ISCO in-situ chemical oxidation-   Lawesson reagent 4-Methoxyphenylthiophosphoric cyclic    di(thioanhydride), LR,    2,4-Bis(4-methoxyphenyl)-2,4-dithioxo-1,3,2,4-dithiadiphosphetane,    2,4-Bis-(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane 2,4-disulfide-   LCMS liquid chromatography mass spectrometry-   LDA Lithium diisopropyl amide-   LiHMDS Lithium bis(trimethylsilyl)amide-   Me Methyl-   MeCN Acetonitrile-   MeI Iodomethane-   MeOH methyl alcohol-   MeOD deuteurated methyl alcohol-   mg Milligrams-   min Min-   mL Milliliters-   Mo—(CO)₆ molybdenum hexacarbonyl-   MTBE methyl tert-butyl ether-   NBS N-bromosuccinimide-   NMP 1-methyl-2-pyrrolidinone-   NMR nuclear magnetic resonance-   NOESY nuclear Overhauser effect spectroscopy-   Pd(dppf)Cl_(2 [)1,1′-Bis(diphenylphosphino)ferrocene]dichloropalladium(II),    complex with dichloromethane-   PMBCl 1-(chloromethyl)-4-methoxybenzene-   PTSA p-toluenesulfonic acid-   Py pyridine-   RT RT-   sat. saturated-   t-bu tert-butyl group-   TFA trifluoroacetic acid-   THF tetrahydrofuran-   TLC thin layer chromatography-   TMSCl Trimethylsilyl chloride-   TBDPS Tert-Butylchlorodiphenyl-   Tol Toluene-   TsCl 4-toluenesulfonyl chloride (CH₃C₆H₄SO₂Cl)-   Xantphos 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene

General Schemes

In general, the compounds of the formula I can be prepared according tothe following General Schemes A to H, wherein m, p, q, R¹, R^(4a),R^(4b), R⁵, Y, X¹, X², X³, X⁴, and X⁵ are defined herein.

Preparation 1

Zinc Dust Preactivation Procedure

Zinc dust (Acros) was slowly added to a well stirred solution of aqueous2N HCl. The material was allowed to stir for 30 min at which point itwas filtered, washed with water, EtOH, and diethyl ether. The materialwas dried using a rotavapor.

STEP 1: TERT-BUTYL 3-(3-BROMOPYRIDIN-2-YL)AZETIDINE-1-CARBOXYLATE (3)

A 5 L 3-neck round bottom flask fitted with a magnetic stirrer undernitrogen was charged with zinc dust (138 g, preactivated according tothe above Preparation 1, 2.11 mol, 2 eq.) and DMA (370 mL, anhydrous).1,2-dibromoethane (13 mL, 0.158 mol, 0.15 eq, Aldrich) was then addedover 5 min, followed by TMSCl (20 mL, 0.158 mol, 0.15 eq, Acros) over 5min. The reaction mixture was stirred for 20 min at RT. A solution ofN-Boc-3-iodoazetidine (2) (448 g, 1.583 mol, 1.5 eq, CNH Technologies)in DMA (925 mL, anhydrous) was added over 25 min keeping the internaltemperature below 65° C. using a water bath. The suspension was stirredfor 1 h at RT at which point it was degassed with nitrogen. Stirring wasstopped and the suspension was allowed to stand. A 12 L 3-neck roundbottom flask fitted with a mechanical stirrer was charged with2,3-dibromopyridine (1) (250 g, 1.055 mol, 1.0 eq, Frontier Scientific),PdCl₂dppf.CH₂Cl₂ (25.8 g, 31.65 mmol, 0.03 eq, Aldrich), CuI (12.5 g,65.41 mmol, 0.062 eq, Aldrich), and DMA (925 mL, anhydrous). Thesolution was degassed with nitrogen. The clear zinc reagent solutionabove the residual solid zinc was poured into the 12 L flask undernitrogen. The brown solution was degassed with nitrogen and heated to80° C. for 17 h at which point LCMS indicated complete conversion of2,3-dibromopyridine (1). The reaction mixture was transferred to brine(2 L) in 22 L separatory funnel. Water (2 L) and EtOAc (4 L) were addedand the layers were separated. The aqueous layer was extracted withEtOAc (2×3 L). The combined organics were washed with water (3×3 L) andbrine (2 L), dried over sodium sulfate and evaporated. The resultingresidue was purified by column chromatography (eluting withhexanes/ethyl acetate=9:1 to 5:1) to obtain 289 g of impure tert-butyl3-(3-bromopyridin-2-yl)azetidine-1-carboxylate (3) which was distilledunder high vacuum to remove the impurity (N-Boc-azetidine) to give 281 gof pure tert-butyl 3-(3-bromopyridin-2-yl)azetidine-1-carboxylate.Yield: 85%.

STEP 2: 2-(AZETIDIN-3-YL)-3-BROMOPYRIDINE HYDROCHLORIDE (4)

To a solution of tert-butyl3-(3-bromopyridin-2-yl)azetidine-1-carboxylate (3) (266 g, 0.849 mol, 1eq.) in methanol (6 L) was added concentrated HCl (350 mL, 4.2 mol, 4.95eq.) and the resulting mixture was stirred at RT for 92 hrs. The mixturewas concentrated and dried using a rotavapor to obtain 230 g of2-(azetidin-3-yl)-3-bromopyridine hydrochloride (4).

STEP 3: 2-(3-(3-BROMOPYRIDIN-2-YL)AZETIDIN-1-YL)QUINOLINE (5)

A mixture of 2-(azetidin-3-yl)-3-bromopyridine hydrochloride (4) (221 g,0.886 mol), 2-chloroquinoline (133.5 g, 0.816 mol, 0.92 eq.,Combi-Blocks) and cesium carbonate (866 g, 2.658 mol, 3 eq.) inanhydrous DMF (7 L) was heated to 110° C. and stirred for 16 hrs. Aftercooling to RT, the mixture was transferred to 50 L separatory funnel anddiluted with water (14 L). The precipitated solid was filtered, stirredin water (4 L), filtered and dried to obtain 222 g of2-(3-(3-bromopyridin-2-yl)azetidin-1-yl)quinoline. Yield: 80% over twosteps.

¹H NMR (300 MHz, d₆-DMSO) δ ppm 8.58 (d, J=4.8 Hz, 1H), 8.11 (d, J=8.1Hz, 1H), 8.04 (d, J=9.0 Hz, 1H), 7.71 (d, J=8.1 Hz, 1H), 7.65-7.50 (m,2H), 7.35-7.15 (m, 2H), 6.81 (d, J=9.0 Hz, 1H), 4.55-4.30 (m, 5H). HPLCpurity: >98% (215 nm and 254 nm)

LCMS: m/z: 340.1 for ⁷⁹Br (M+1), Calcd. for C₁₇H₁₄ ⁷⁹BrN₃: 339.04; 342.1for ⁸¹Br (M+1), Calcd. for C₁₇H₁₄ ⁸¹BrN₃: 341.04.

Preparation 2

STEP 1: TERT-BUTYL 3-(3-CHLOROPYRAZIN-2-YL)AZETIDINE-1-CARBOXYLATE (7)

A 12 L 3-neck round bottom flask fitted with a magnetic stirrer undernitrogen was charged with zinc dust (745 g, preactivated according tothe above Preparation 1, 11.4 mol, 2 eq.) and DMA (2 L, anhydrous).1,2-dibromoethane (71 mL, 0.855 mol, 0.15 eq, Aldrich) was then addedover 10 min, followed by TMSCl (108 mL, 0.855 mol, 0.15 eq, Acros) over20 min. The reaction mixture was stirred for 25 min at RT. A solution ofN-Boc-3-iodoazetidine (2) (2420 g, 8.55 mol, 1.5 eq, CNH Technologies)in DMA (5 L, anhydrous) was added via a 2 L addition funnel over 2 hkeeping the internal temperature below 65° C. using a water bath. Thesuspension was stirred for 1 h at RT at which point it was degassed withnitrogen. Stirring was stopped and the suspension was allowed to stand.A 22 L 3-neck round bottom flask fitted with a mechanical stirrer wascharged with 2,3-dichloropyrazine (6) (850 g, 5.70 mol, 1.0 eq, AKScientific), PdCl₂dppf.CH₂Cl₂ (140 g, 171 mmol, 0.03 eq, Aldrich), CuI(67.3 g, 353 mmol, 0.062 eq, Aldrich), and DMA (5 L, anhydrous). Thesolution was degassed with nitrogen. The clear zinc reagent solutionabove the residual solid zinc was poured into the 22 L flask undernitrogen. The brown solution was degassed with nitrogen and heated to80° C. for 16 h at which point LCMS indicated complete conversion of2,3-dichloropyrazine (6). The reaction mixture was transferred to brine(8 L) in 50 L reparatory funnel. Water (8 L) and EtOAc (15 L) were addedand the layers were separated. The aqueous layer was extracted withEtOAc (2×10 L). The combined organics were washed with water (3×10 L)and brine (5 L), dried over sodium sulfate and evaporated. The resultingresidue was purified by column chromatography (eluting withhexanes/ethyl acetate=10:1) to obtain 536 g of pure tert-butyl3-(3-chloropyrazin-2-yl)azetidine-1-carboxylate (7) and 121 g of mixedfractions. The impure material was distilled under high vacuum to removethe impurity (N-Boc-azetidine) to give 81 g of pure tert-butyl3-(3-chloropyrazin-2-yl)azetidine-1-carboxylate (7).

Total: 617 g, Yield: 40%.

STEP 2: 2-(AZETIDIN-3-YL)-3-CHLOROPYRAZINE HYDROCHLORIDE (8)

To a solution of tert-butyl3-(3-chloropyrazin-2-yl)azetidine-1-carboxylate (7) (300 g, 1.112 mol, 1eq.) in methanol (6 L) was added concentrated HCl (400 mL, 4.8 mol, 4.3eq.) and the resulting mixture was stirred at RT for 112 h. The mixturewas concentrated and dried on rotavapor to obtain 230 g of2-(azetidin-3-yl)-3-chloropyrazine hydrochloride (8).

STEP 3: 2-(3-(3-CHLOROPYRAZIN-2-YL)AZETIDIN-1-YL)QUINOLINE (9)

A mixture of 2-(azetidin-3-yl)-3-chloropyrazine hydrochloride (8) (163g, 0.79 mol), 2-bromoquinoline (164 g, 0.79 mol, 1 eq., Combi-Blocks)and cesium carbonate (772 g, 2.37 mol, 3 eq., Aldrich) in anhydrous DMF(6.5 L) was heated to 110° C. and stirred for 19 h. After cooling to RT,the mixture was transferred to 50 L separatory funnel and diluted withwater (13 L). Then it was extracted with ethyl acetate (20 L×2) and theorganic extracts were combined, washed with water (8 L), brine (8 L),dried and concentrated. The resulting residue was purified by columnchromatography (eluting with hexanes/ethyl acetate=9:1 to 3:1). Allfractions containing desired compound were combined and concentrated.The obtained solid was triturated with MTBE (250 mL), washed with MTBE(100 mL×2) and dried to obtain 100 g of2-(3-(3-chloropyrazin-2-yl)azetidin-1-yl)quinoline (9) with >99% purity.The mother liquor was concentrated and purified by column chromatographyand trituration with MTBE again to give 4.5 g of2-(3-(3-chloropyrazin-2-yl)azetidin-1-yl)quinoline (9) with >99% purity.Yield: 45% for two steps.

¹H NMR (300 MHz, d₆-DMSO) δ ppm 8.67 (d, J=2.4 Hz, 1H), 8.44 (d, J=2.4Hz, 1H), 8.04 (d, J=9.6 Hz, 1H), 7.72 (d, J=8.4 Hz, 1H), 7.65-7.50 (m,2H), 7.23 (t, J=7.35 Hz, 2H), 6.79 (d, J=9.0 Hz, 1H), 4.60-4.30 (m, 5H).HPLC purity: >99% (215 nm and 254 nm) LCMS: m/z: 297.1 (M+1), Calcd. forC₁₆H₁₃ClN₄: 296.08.

Preparation 3

2-(3-(3-CHLOROPYRAZIN-2-YL)AZETIDIN-1-YL)QUINAZOLINE (10)

2-(Azetidin-3-yl)-3-chloropyrazine hydrochloride (8) (1.50 g, 7.28mmol), 2-chloroquinazoline (1.20 g, 7.28 mmol, Parkway Scientific), andcesium carbonate (5.22 g, 16.0 mmol, Fluka) were mixed in DMF (30 mL) ina round bottom flask under a nitrogen atmosphere. The mixture wasstirred at 110° C. for 17 h. The reaction mixture was cooled to RT,diluted with water, and extracted with EtOAc (2×). The combined organicextracts were washed with saturated sodium chloride, dried overmagnesium sulfate, filtered, and concentrated in vacuo. The resultingcrude mixture was purified via silica gel flash column chromatographyeluting with 0% to 100% EtOAc in hexanes to give 1.02 g (47%) of ayellow amorphous solid.

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 4.41-4.50 (m, 1H) 4.58-4.63 (m, 2H)4.65-4.72 (m, 2H) 7.22-7.28 (m, 1H) 7.61-7.72 (m, 3H) 8.28 (d, J=2.35Hz, 1H) 8.51 (d, J=2.35 Hz, 1H) 9.04 (s, 1H). ESI (M+1) 298.1; calc forC₁₅H₁₂ClN₅ 297.

Preparation 4

STEP 1. 3-(3-MORPHOLIN-4-YL-PYRAZIN-2-YL)-AZETIDINE-1-CARBOXYLIC ACIDTERT-BUTYL ESTER (11)

A mixture of 3-(3-chloro-pyrazin-2-yl)-azetidine-1-carboxylic acidtert-butyl ester (7) (269 mg, 1.0 mmol) in morpholine was heated bymicrowave at 160° C. for 2 h. The mixture was concentrated to give thecrude compound and which was purified by column chromatography to affordpure product (11) (300 mg, yield 94%) as solid. ESI-MS (M+1): 321 calc.for C₁₆H₂₄N₄O₃ 320.

STEP 2. 4-(3-AZETIDIN-3-YL-PYRAZIN-2-YL)-MORPHOLINE HYDROCHLORIDE (12)

To a solution of 4 N HCl/MeOH (10 mL) was added compound (II) (300 mg,0.90 mmol) at 0° C. and the resulting mixture was stirred at RT for 1 h.The mixture was concentrated under reduced pressure to give (12) (200mg, yield 100%), which was used directly for the next step withoutfurther purification. ESI-MS (M+1): 221 calc. for C₁₁H₁₆N₄O 220.

The following Table 1 lists compounds of Preparation P4.1 to P4.4, whichwere made analogous to Preparation 4 by using the appropriate materials.

TABLE 1 PREPARATION P4.1 TO P4.4 ESI-MS Prep. # Structure Chemical Name(M + 1) P4.1

tert-butyl 3-(3-morpholinopyrazin-2- yl)azetidin-1-carboxylate 321 P4.2

tert-butyl 3-(3-(4-hydroxypiperidin-1- yl)pyrazin-2-yl)azetidine-1-carboxylate 335 P4.3

4-(3-azetidin-3-yl-pyrazin-2-yl)- morpholine hydrochloride 221 P4.4

1-(3-(azetidin-3-yl)pyrazin-2- yl)piperidin-4-ol hydrochloride 235

Preparation 5

STEP 1. 3-[3-(2-METHOXY-PHENOXY)-PYRAZIN-2-YL]-AZETIDINE-1-CARBOXYLICACID TERT-BUTYL ESTER (13)

A mixture of 3-(3-chloro-pyrazin-2-yl)-azetidine-1-carboxylic acidtert-butyl ester (7) (100 mg, 0.37 mmol), 2-methoxy-phenol (47 mg, 0.37mmol) and Cs₂CO₃ (242 mg, 0.74 mmol) in DMSO (10 mL) was stirred at 90°C. overnight. The mixture was diluted with water and extracted withEtOAc. The organic layer was washed with brine, dried over Na₂SO₄ andconcentrated to give the crude compound, which was purified by columnchromatography to afford pure product (13) (80 mg, 0.22 mmol, yield 61%)as solid. ESI-MS (M+1): 358 calc. for C₁₉H₂₃N₃O₄ 357.

STEP 2. 2-AZETIDIN-3-YL-3-(2-METHOXY-PHENOXY)-PYRAZINE HYDROCHLORIDE(14)

To a solution of 4 N HCl/MeOH (10 mL) was added compound (13) (80 mg,0.22 mmol) at 0° C. The resulting mixture was stirred at RT for 1 h. Themixture was concentrated under reduced pressure to give (14) (65 mg,yield 100%), which was used for the next step without furtherpurification. ESI-MS (M+1): 258 calc. for C₁₄H₁₅N₃O₂ 257.

The following Table 2 lists compounds of Preparation P5.1 to P5.8, whichwere made analogous to Preparation 5 by using the appropriate materials.

TABLE 2 PREPARATION P5.1 TO P5.8 ESI-MS Ex. # Structure Chemical Name(M + 1) P5.1

3-[3-(2-methoxy-phenoxy)-pyrazin- 2-yl]-azetidine-1-carboxylic acidtert-butyl ester 358 P5.2

tert-butyl 3-(3-(3- methoxyphenoxy)pyrazin-2- yl)azetidin-1-carboxylate358 P5.3

tert-butyl 3-(3-(4- methoxyphenoxy)pyrazin-2- yl)azetidine-1-carboxylate358 P5.4

tert-butyl 3-(3-phenoxypyrazin-2- yl)azetidine-1-carboxylate 328 P5.5

2-azetidin-3-yl-3-(2-methoxy- phenoxy)-pyrazine hydrochloride 258 P5.6

2-(azetidin-3-yl)-3-(3- methoxyphenoxy)pyrazine hydrochloride 258 P5.7

2-(azetidin-3-yl)-3-(4- methoxyphenoxy)pyrazine hydrochloride 258 P5.8

2-(azetidin-3-yl)-3- phenoxypyrazine hydrochloride 228

Preparation 6

STEP 1. 2-TRICHLOROMETHYL-1H-BENZOIMIDAZOLE (17)

2,2,2-trichloro-acetimidic acid benzyl ester (16) (2.3 g, 9.22 mmol,Alfa Aesar) was added to a solution of Benzene-1,2-diamine (15) (1.0 g,9.2 mmol) in acetic acid (30 mL), the solution was stirred at RT for 1h. H₂O (20 mL) was added to the mixture and the suspension was filtered.The filter cake was washed with water and dried under vacuum to affordcompound (17) (1.90 g yield 88%) which was used directly for the nextstep without further purification. ESI-MS (M+1): 235 calc. for C₈H₅Cl₃N₂234.

STEP 2. 1H-BENZOIMIDAZOLE-2-CARBOXYLIC ACID METHYL ESTER (18)

Na₂CO₃ (0.64 g, 6.07 mmol) was added to a solution of (17) (1.9 g, 6.07mmol) in 20 mL MeOH. The reaction mixture was heated to reflux for 14 hand then cooled to RT. 1N HCl was added to the solution and the reactionmixture was stirred for 0.5 hour. The mixture was extracted with EA. Theorganic phase was washed with brine, dried over Na₂SO₄ and evaporated togive the title compound (0.89 g, yield 83%). ESI-MS (M+1): 177 calc. forC₉H₈N₂O₂ 176.

STEP 3. 1H-BENZOIMIDAZOLE-2-CARBOXYLIC ACID (19)

A mixture of 1H-benzoimidazole-2-carboxylic acid methyl ester (18) (0.89g, 5.1 mmol) in 2 N aq. NaOH (10 mL) and MeOH (10 mL) was stirred at RTfor 18 h. The mixture was acidified to pH=4 with 1 N aqueous HCl. Themixture was extracted with EtOAc. The organic layer was washed withbrine, dried over Na₂SO₄ and evaporated to obtain compound (19) as abrown solid (0.67 g, yield 80%). ESI-MS (M+1): 163 calc. for C₈H₆N₂O₂162.

The following Table 3 lists compounds of Preparation P6.1 to P6.18,which were made analogous to Preparation 6 by using the appropriatematerials.

TABLE 3 PREPARATION P6.1 TO P6.18 ESI-MS Ex. # Structure Chemical Name(M + 1) P6.1 

4-chloro-2-(trichloromethyl)-1H- benzo[d]imidazole 268 P6.2 

5-chloro-2-(trichloromethyl)-1H- benzo[d]imidazole 268 P6.3 

4-fluoro-2-(trichloromethyl)-1H- benzo[d]imidazole 252 P6.4 

5-fluoro-2-(trichloromethyl)-1H- benzo[d]imidazole 252 P6.5 

4-methyl-2-(trichloromethyl)-1H- benzo[d]imidazol 249 P6.6 

5-methyl-2-(trichloromethyl)-1H- benzo[d]imidazole 249 P6.7 

methyl 4-chloro-1H- benzo[d]imidazole-2-carboxylate 211 P6.8 

methyl 5-chloro-1H- benzo[d]imidazole-2-carboxylate 211 P6.9 

methyl 4-fluoro-1H- benzo[d]imidazole-2-carboxylate 195 P6.10

methyl 5-fluoro-1H- benzo[d]imidazole-2-carboxylate 195 P6.11

methyl 4-methyl-1H- benzo[d]imidazole-2-carboxylate 191 P6.12

methyl 5-methyl-1H- benzo[d]imidazole-2-carboxylate 191 P6.13

4-chloro-1H-benzo[d]imidazole-2- carboxylic acid 197 P6.14

5-chloro-1H-benzo[d]imidazole-2- carboxylic acid 197 P6.15

4-fluoro-1H-benzo[d]imidazole-2- carboxylic acid 181 P6.16

5-fluoro-1H-benzo[d]imidazole-2- carboxylic acid 181 P6.17

4-methyl-1H-benzo[d]imidazole-2- carboxylic acid 177 P6.18

5-methyl-1H-benzo[d]imidazole-2- carboxylic acid 177

Preparation 7

STEP 1. 3-[3-(4-METHOXY-PHENYL)-PYRAZIN-2-YL]-AZETIDINE-1-CARBOXYLICACID TERT-BUTYL ESTER (21)

To a solution of 3-(3-chloro-pyrazin-2-yl)-azetidine-1-carboxylic acidtert-butyl ester (7) (100 mg, 0.37 mmol, as prepared in the abovePreparation 2) in dioxane (8 mL) was added a solution of Na₂CO₃ (78 mg,0.64 mmol) in 0.5 mL water, followed by additional of4-methoxybenzeneboronic acid (20) (49 mg 0.40 mmol) and Pd(dppf)Cl₂ (8mg). The resulting mixture was heated to reflux overnight under N₂atmosphere. TLC showed that the starting material was consumedcompletely. The solution was filtered and the filtrate was concentratedto give the residue which was purified by column chromatography onsilica gel to give the product compound (21) (120 mg, yield 96%) assolid. ESI-MS (M+1): 342 calc. for C₁₉H₂₃N₃O₃ 341.

STEP 2. 2-AZETIDIN-3-YL-3-(4-METHOXY-PHENYL)-PYRAZINE HYDROCHLORIDE (22)

To a solution of 4 N HCl in MeOH (10 mL) was added (21) (120 mg, 0.35mmol) at 0° C. and the resulting mixture was stirred at RT for 1 h. Themixture was concentrated under reduced pressure to give2-azetidin-3-yl-3-(4-methoxy-phenyl)-pyrazine (22) (95 mg, yield 100%)which was used for the next step without further purification. ESI-MS(M+1): 242 calc. for C₁₄H₁₅N₃O 241.

The following Table 4 lists compounds of Preparation P7.1 to P7.6, whichwere made analogous to Preparation 7 by using the appropriate materials.

TABLE 4 PREPARATION P7.1 TO P7.6 ESI- MS Ex. # Structure Chemical Name(M + 1) P7.1

tert-butyl 3-(3-(4- methoxyphenyl) pyrazin-2-yl) azetidine-1-carboxylate342 P7.2

tert-butyl 3-(3-(2- methoxyphenyl) pyrazin-2-yl) azetidine-1-carboxylate342 P7.3

tert-butyl 3-(3- phenylpyrazin-2- yl)azetidine-1- carboxylate 312 P7.4

2-(azetidin-3-yl)- 3-(4-methoxyphenyl) pyrazine hydrochloride 242 P7.5

2-(azetidin-3-yl)- 3-(2-methoxyphenyl) pyrazine hydrochloride 242 P7.6

2-(azetidin-3-yl)-3- phenylpyrazine hydrochloride 212

Preparation 8

STEP 1. TERT-BUTYL 3-(2-FLUOROPYRIDIN-3-YL)AZETIDINE-1-CARBOXYLATE (25)

To a 2 L 3 necked round bottomed flask fitted with a mechanical stirrer,under nitrogen atmosphere was placed Zinc dust, which was preactivatedaccording to above Preparation 2, (51.2 g, 0.78 mol, 1.94 eq) anddimethyl acetamide (162 mL). To the above suspension, 1,2-dibromoethane(12.14 g, 0.0646 mol, 0.16 eq) was added dropwise at RT (exotherm andbubbling were observed), followed by dropwise addition of TMSCl (6.99 g,0.0646 mol, 0.16 eq). A vigorous reaction (exotherm to 55° C.) wasobserved. To this, a solution of N-Boc-3-iodoazetidine (2) (182.88 g,0.646 mol, 1.6 eq) in dimethyl acetamide (378 mL) was added dropwiseusing an addition funnel (exotherm to 50° C. was observed). Thesuspension was stirred for 1.5 h at RT and was then degassed withnitrogen for 15 min. Stirring was stopped and suspension was allowed tostand under nitrogen. To a 5 L 3 necked round bottomed flask, fittedwith mechanical stirrer, flushed with nitrogen were placed3-iodo-2-fluoropyridine (24) (90 g, 0.404 mol, 1.0 eq), PdCl₂dppf.CH₂Cl₂(9.88 g, 0.012 mol, 0.03 eq), CuI (4.76 g, 0.025 mol, 0.062 eq) anddimethyl acetamide (396 mL). The red colored suspension was degassedwith nitrogen for 15 min.

The Zinc reagent solution in 2 L flask was cannulated into 5 L roundbottomed flask. The resulting reaction mixture was degassed again withnitrogen for 15 min with stirring and heated to 80° C. for overnightunder nitrogen. LCMS indicates completion of reaction. The reaction wascooled to RT and quenched by addition of brine solution (1 L). To thisEtOAc (1 L) and water (1 L) were added and layers were separated. Theaqueous layer was extracted with EtOAc (2×2 L). The combined EtOAclayers were washed with water (2 L), brine (1 L), dried (Na₂SO₄),filtered, and evaporated. The crude was purified by columnchromatography to give 52 g of tert-butyl3-(2-fluoropyridin-3-yl)azetidine-1-carboxylate (25) (yield: 51%) as anoil, which solidified on standing.

¹H NMR (300 MHz CDCl₃): 8.13 (doublet, J=4.8 Hz, 1H), 7.83-7.76 (dt,1H), 7.28-7.20 (dt, 1H), 4.35 (t, J=8.7 Hz, 2H), 4.05-3.88 (m, 3H), 1.46(s, 9H). LC-MS: 253 (M+1); calcd for C₁₃H₁₇FN₂O₂: 252.28

STEP 2. 3-(2-PHENYL-PYRIDIN-3-YL)-AZETIDINE-1-CARBOXYLIC ACID TERT-BUTYLESTER (27)

To a solution of 3-(2-fluoro-pyridin-3-yl)-azetidine-1-carboxylic acidtert-butyl ester (25) (200 mg, 0.80 mmol), Ni(acac)₂ (20 mg, 0.08 mmol),DPPF (32 mg, 0.08 mmol) in THF (10 mL) was added PhMgBr (1 M, 0.8 mL,0.80 mmol). The resulting mixture was heated to reflux overnight underN₂ atmosphere. TLC showed that the staring material was consumedcompletely. The solution was filtered and the filtrate was concentratedto give the residue, The crude compound was purified by columnchromatography on silica gel to give the product 3compound (27) (180 mg,yield 78%) as solid. ESI-MS (M+1): 311 calc. for C₁₉H₂₂N₂O₂ 310.

STEP 3. 3-AZETIDIN-3-YL-2-PHENYL-PYRIDINE HYDROCHLORIDE (28)

To a solution of 4 M HCl in MeOH (10 mL) was added3-(2-phenyl-pyridin-3-yl)-azetidine-1-carboxylic acid tert-butyl ester(27) (180 mg, 0.58 mmol) at 0° C. and the resulting mixture was stirredat RT for 1 h. The mixture was concentrated under reduced pressure togive 3-azetidin-3-yl-2-phenyl-pyridine hydrochloride (28) (120 mg, yield94%) which was used for the next step without further purification.ESI-MS (M+1): 211 calc. for C₁₄H₁₄N₂ 210.

Preparation 9

STEP 1. 3-(3-M-TOLYL-PYRAZIN-2-YL)-AZETIDINE-1-CARBOXYLIC ACIDTERT-BUTYL ESTER (30)

To a solution of 3-(3-chloro-pyrazin-2-yl)-azetidine-1-carboxylic acidtert-butyl ester (7) (540 mg, 2.0 mmol, Preparation 2),3-methyl-phenylboronic acid (78) (299.2 mg, 2.2 mmol), K₃PO₄ (818 mg,4.0 mmol), in dioxane (20 mL) and water (4 mL) was added Pd(dppf)Cl₂(73.2 mg, 0.1 mmol) then the reaction mixture was stirred at 90° C.under nitrogen atmosphere overnight. The reaction mixture was filteredthrough CELITE® and washed with EtOAc (50 mL). The filtrate wasconcentrated and the crude product was purified by silica gel column togive 3-(3-m-tolyl-pyrazin-2-yl)-azetidine-1-carboxylic acid tert-butylester (30) (597 mg, 1.84 mmol, yield 91.85%).

ESI-MS (M+1): 326 calc. for C₁₉H₂₃N₃O₂ 325.

STEP 2. 2-AZETIDIN-3-YL-3-M-TOLYL-PYRAZINE HYDROCHLORIDE (31)

A solution of 3-(3-m-tolyl-pyrazin-2-yl)-azetidine-1-carboxylic acidtert-butyl ester (30) (325 mg, 1.0 mmol) in 4N HCl/MeOH (20 mL) wasstirred at RT for 30 min. The reaction mixture was concentrated to give(31) (260 mg, 0.99 mmol, yield 99.24%).

ESI-MS (M+1): 226 calc. for C₁₄H₁₅N₃ 225.

Preparation 10

STEP 1. 3-[3-(3-METHOXY-PHENYL)-PYRAZIN-2-YL]-AZETIDINE-1-CARBOXYLICACID TERT-BUTYL ESTER (33)

To a solution of 3-(3-chloro-pyrazin-2-yl)-azetidine-1-carboxylic acidtert-butyl ester (7) (540 mg, 2.0 mmol, Preparation 2),3-methoxy-phenylboronic acid (29) (334.4 mg, 2.2 mmol), K₃PO₄ (818 mg,4.0 mmol), in dioxane (20 mL) and water (4 mL) was added Pd(dppf)Cl₂(73.2 mg, 0.1 mmol) then the reaction mixture was stirred at 90° C.under nitrogen atmosphere overnight. The reaction mixture was filteredthrough CELITE® and washed with EtOAc (50 mL). The filtrate wasconcentrated and the crude product was purified by silica gel column togive compound (33) (627.4 mg, 1.84 mmol, yield 91.85%).

ESI-MS (M+1): 342 calc. for C₁₉H₂₃N₃O₃ 341.

STEP 2. 2-AZETIDIN-3-YL-3-(3-METHOXY-PHENYL)-PYRAZINE HYDROCHLORIDE (34)

A solution of (33) (341 mg, 1.0 mmol) in 4N HCl/MeOH (20 mL) was stirredat RT for 30 min. The reaction mixture was concentrated to give (34)(260 mg, 0.99 mmol, yield 99.24%).

ESI-MS (M+1): 242 calc. for C₁₄H₁₅N₃O 241.

Preparation 11

STEP 1.3-[3-(4-HYDROXYMETHYL-PIPERIDIN-1-YL)-PYRAZIN-2-YL]-AZETIDINE-1-CARBOXYLICACID TERT-BUTYL ESTER (36)

To a solution of compound (7) (540 mg, 2 mmol, Preparation 2) and4-amino-2-methyl-butan-1-ol (230 mg, 2 mmol) in DMSO (20 mL) was addedEt₃N (404 mg, 4 mmol). The reaction mixture was stirred at 110° C.overnight. The reaction mixture was diluted with water, extracted withEtOAc (50 mL×3). The combined organic extracts were washed with water(30 mL) and brine (30 mL), dried over Na₂SO₄ and filtered. The filtratewas evaporated in vacuo and the residue was purified by flash columnchromatography (EtOAc: Petrol ether=3:1) on silica gel to give (36).(557 mg, 1.6 mmol, yield 80%).

ESI-MS (M+1): 349 calc. for C₁₈H₂₈N₄O₃ 348.

STEP 2. [1-(3-AZETIDIN-3-YL-PYRAZIN-2-YL)-PIPERIDIN-4-YL]-METHANOLHYDROCHLORIDE (37)

A solution of (36) (557 mg, 1.6 mmol) in 4N HCl/MeOH (20 mL) was stirredat RT for 30 min. The reaction mixture was concentrated to give (37)(450 mg, 1.58 mmol, yield 98%).

ESI-MS (M+1): 249 calc. for C₁₃H₂₀N₄O 248.

Preparation 12

STEP 1. 4-(3-CHLORO-PYRAZIN-2-YL)-PIPERIDINE-1-CARBOXYLIC ACIDTERT-BUTYL ESTER (39)

A 100 mL 3-neck round bottom flask fitted with a magnetic stirrer andflushed with nitrogen was charged with zinc dust (813 mg, preactivatedaccording to the above Preparation 1, 12.7 mmol, 2.0 eq.) and DMA (10mL, anhydrous). 1,2-dibromoethane (236 mg, 1.27 mmol, 0.2 eq) was addedslowly, followed by TMSCl (137 mg, 1.27 mmol, 0.2 eq). The reaction wasstirred for 15 min at RT. A solution of 4-iodo-piperidine-1-carboxylicacid tert-butyl ester (38) (2.95 g, 9.5 mmol, 1.5 eq) in DMA (10 mL,anhydrous) was added dropwise. The suspension was stirred for 1 h at RT.

A 100 mL 3-neck round bottom flask fitted with a mechanical stirrer wascharged with 2,3-dichloro-pyrazine (6) (0.95 g, 6.4 mmol, 1.0 eq),Pd(dppf)Cl₂ (446 mg, 0.64 mmol, 0.1 eq), cuprous iodide (121 mg, 0.64mmol, 0.1 eq), and DMA (20 mL, anhydrous). The dark solution wasdegassed for 15 min. The clear zinc reagent solution above the residualsolid zinc was transferred to the above 100 mL flask by cannulation. Thedark solution was degassed and heated to 80° C. for 16 h. The reactionwas diluted with brine and extracted with EtOAc (3×100 mL). The combinedorganics were washed with water (2×100 mL) and brine (100 mL), followedby drying over sodium sulfate. The solution was concentrated and theresidue was purified by flash column chromatography on silica gel(PE:EAOAc=2:1) to give the title compound (39) (0.95 g, 3.2 mmol, 50%yield) as a light yellow solid.

ESI-MS (M+1): 298 calc. for C₁₄H₂₀ClN₃O₂ 297.

STEP 2.4-[3-(4-HYDROXYMETHYL-PIPERIDIN-1-YL)-PYRAZIN-2-YL]-PIPERIDINE-1-CARBOXYLICACID TERT-BUTYL ESTER (40)

To a solution of 4-(3-chloro-pyrazin-2-yl)-piperidine-1-carboxylic acidtert-butyl ester (39) (297 mg, 1 mmol) and piperidin-4-yl-methanol (35)(126.5 mg, 1.1 mmol) in DMSO (6 mL) was added Et₃N (202 mg, 2 mmol). Thereaction mixture was stirred at 100° C. overnight. The reaction mixturewas diluted with water, extracted with EtOAc (30 mL×3). The combinedorganic extracts were washed with water (30 mL) and brine (30 mL), driedover Na₂SO₄ and filtered. The filtrate was evaporated in vacuo and theresidue was purified by flash column chromatography on silica gel togive compound (40) (302 mg, 0.8 mmol, yield 80.32%).

ESI-MS (M+1): 377 calc. for C₂₀H₃₂N₄O₃ 376.

STEP 3. [1-(3-PIPERIDIN-4-YL-PYRAZIN-2-YL)-PIPERIDIN-4-YL]-METHANOLHYDROCHLORIDE (41)

A solution of4-[3-(4-hydroxymethyl-piperidin-1-yl)-pyrazin-2-yl]-piperidine-1-carboxylicacid tert-butyl ester (40) (376 mg, 1 mmol) in 4N HCl/MeOH (20 mL) wasstirred at RT for 30 min. The reaction mixture was concentrated to give(41) (308 mg, 0.98 mmol, yield 98.72%).

ESI-MS (M+1): 277 calc. for C₁₅H₂₄N₄O 276.

Preparation 13

STEP 1.3-[3-(3-METHYL-PYRROLIDIN-1-YL)-PYRAZIN-2-YL]-AZETIDINE-1-CARBOXYLICACID TERT-BUTYL ESTER (43)

To a solution of 3-(3-chloro-pyrazin-2-yl)-azetidine-1-carboxylic acidtert-butyl ester (7) (200 mg, 0.74 mmol, Preparation 2) and3-methyl-pyrrolidine (42) (69.2 mg, 0.84 mmol) in DMSO (5 mL) was addedEt₃N (149.5 mg, 1.48 mmol). The reaction mixture was stirred at 100° C.overnight. The reaction mixture was diluted with water, extracted withEtOAc (30 mL×3). The combined organic extracts were washed with water(30 mL) and brine (30 mL), dried over Na₂SO₄ and filtered. The filtratewas evaporated in vacuo and the residue was purified by flash columnchromatography on silica gel to give3-[3-(3-methyl-pyrrolidin-1-yl)-pyrazin-2-yl]-azetidine-1-carboxylicacid tert-butyl ester (43) (194 mg, 0.56 mmol, yield 75.99%).

ESI-MS (M+1): 319 calc. for C₁₇H₂₆N₄O₂ 318

STEP 2. 2-AZETIDIN-3-YL-3-(3-METHYL-PYRROLIDIN-1-YL)-PYRAZINEHYDROCHLORIDE (44)

A solution of3-[3-(3-methyl-pyrrolidin-1-yl)-pyrazin-2-yl]-azetidine-1-carboxylicacid tert-butyl ester (43) (191 mg, 0.6 mmol) in 4N HCl/MeOH (13 mL) wasstirred at RT for 30 min. The reaction mixture was concentrated to give2-azetidin-3-yl-3-(3-methyl-pyrrolidin-1-yl)-pyrazine hydrochloride (44)

(150 mg, 0.59 mmol, yield 99%).

ESI-MS (M+1): 219 calc. for C₁₂H₁₈N₄ 218

Preparation 14

3-(3-CHLORO-QUINOXALIN-2-YL)-AZETIDINE-1-CARBOXYLIC ACID TERT-BUTYLESTER (46)

A 100 mL 3-neck round bottom flask fitted with a magnetic stirrer andflushed with nitrogen was charged with zinc dust (1.3 g, preactivatedaccording to the above Preparation 1, 20 mmol, 2.0 eq.) and DMA (10 mL,anhydrous). 1,2-Dibromoethane (400 mg, 2.0 mmol, 0.2 eq) was addedslowly, followed by TMSCl (240 mg, 2.0 mmol, 0.2 eq). The reaction wasstirred for 15 min at RT. A solution of N-Boc-3-iodoazetidine (2) (4 g,16 mmol, 1.6 eq) in DMA (10 mL, anhydrous) was added dropwise. Thesuspension was stirred for 1 h at RT.

A 100 mL 3-neck round bottom flask fitted with a mechanical stirrer wascharged with 2,3-dichloro-quinoxaline (44) (2 g, 10 mmol, 1.0 eq),Pd(dppf)Cl₂ (800 mg, 1.0 mmol, 0.1 eq), cuprous iodide (200 mg, 1.0mmol, 0.1 eq), and DMA (20 mL, anhydrous). The dark solution wasdegassed for 15 min. The clear zinc reagent solution above the residualsolid zinc was transferred to the above 100 mL flask by cannulation. Thedark solution was degassed and heated to 80° C. for 16 h. The reactionwas diluted with brine and extracted with EtOAc (3×100 mL). The combinedorganics were washed with water (2×100 mL) and brine (100 mL), followedby drying over sodium sulfate. The solution was concentrated and theresidue was purified by flash column chromatography (PE:EAOAc=2:1)provides 3-(3-chloro-quinoxalin-2-yl)-azetidine-1-carboxylic acidtert-butyl ester (46) (1.43 g, 4.5 mmol, 45% yield) as a light yellowsolid.

ESI-MS (M+1): 320 calc. for C₁₆H₁₈ClN₃O₂ 319.

Preparation 15

STEP 1.3-[3-(4-HYDROXYMETHYL-PIPERIDIN-1-YL)-QUINOXALIN-2-YL]-AZETIDINE-1-CARBOXYLICACID TERT-BUTYL ESTER (47)

To a solution of 3-(3-chloro-quinoxalin-2-yl)-azetidine-1-carboxylicacid tert-butyl ester (46) (638 mg, 2 mmol, Preparation 14) andpiperidin-4-yl-methanol (253 mg, 2.2 mmol) in DMSO (10 mL) was addedEt₃N (404 mg, 4 mmol). The reaction mixture was stirred at 140° C. inmicrowave heating for 4 h. The reaction mixture was diluted with water,extracted with EtOAc (30 mL×3). The combined organic extracts werewashed with water (30 mL) and brine (30 mL), dried over Na₂SO₄ andfiltered. The filtrate was evaporated in vacuo and the residue waspurified by flash column chromatography on silica gel to give (47) (670mg, 1.68 mmol, yield 84.15%). ESI-MS (M+1): 399 calc. for C₁₇H₂₂N₄O 398.

STEP 2. [1-(3-AZETIDIN-3-YL-QUINOXALIN-2-YL)-PIPERIDIN-4-YL]-METHANOLHYDROCHLORIDE (48)

A solution of (47) (670 mg, 1.68 mmol) in 4N HCl/MeOH (25 mL) wasstirred at RT for 30 min. The reaction mixture was concentrated to give[1-(3-azetidin-3-yl-quinoxalin-2-yl)-piperidin-4-yl]-methanolhydrochloride (48) (560 mg, 1.67 mmol, yield 99%).

ESI-MS (M+1): 299 calc. for C₁₇H₂₂N₄O 298.

Preparation 16

STEP 1. 2-AZETIDIN-3-YL-3-CHLORO-PYRAZINE HYDROCHLORIDE (8)

A solution of compound (7) (540 mg, 2.0 mmol) in 2N HCl/MeOH (20 mL) wasstirred at RT for 30 min according to Preparation 2. The reactionmixture was concentrated to give compound (8) (440 mg, 1.99 mmol, yield99.7%).

ESI-MS (M+1): 170 calc. for C₇H₈ClN₃ 169.

STEP 2.4-(3-AZETIDIN-3-YL-PYRAZIN-2-YL)-3,6-DIHYDRO-2H-PYRIDINE-1-CARBOXYLICACID TERT-BUTYL ESTER (50)

To a solution of (8) (442 mg, 2.0 mmol), 4-phenylboronicacid-3,6-dihydro-2H-pyridine-1-carboxylic acid tert-butyl ester (49)(679.8 mg, 2.2 mmol), K₃PO₄ (818 mg, 4.0 mmol) in dioxane (20 mL) andwater (4 mL) was added Pd(dppf)Cl₂ (73.2 mg, 0.1 mmol) then the reactionmixture was stirred at 90° C. under nitrogen atmosphere overnight. Thereaction mixture was filtered through CELITE® and washed with EtOAc (50mL). The filtrate was concentrated and the crude product was purified bysilica gel column to give (50) (540 mg, 1.7 mmol, yield 85%).

ESI-MS (M+1): 317 calc. for C₁₇H₂₄N₄O₂ 316.

STEP 3. 4-(3-AZETIDIN-3-YL-PYRAZIN-2-YL)-PIPERIDINE-1-CARBOXYLIC ACIDTERT-BUTYL ESTER (51)

To a solution of4-(3-azetidin-3-yl-pyrazin-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylicacid tert-butyl ester (50) (540 mg, 1.7 mmol) in MeOH was added Pd/C(10%, 0.5 g) under nitrogen. The reaction was stirred under hydrogen (30psi) at RT for 6 h. Filtered to remove Pd/C and concentrated to drynessto give 4-(3-azetidin-3-yl-pyrazin-2-yl)-piperidine-1-carboxylic acidtert-butyl ester (51) (502 mg, 1.58 mmol yield 92.9%).

ESI-MS (M+1): 319 calc. for C₁₇H₂₆N₄O₂ 318.

STEP 4.4-[3-(1-QUINOLIN-2-YL-AZETIDIN-3-YL)-PYRAZIN-2-YL]-PIPERIDINE-1-CARBOXYLICACID TERT-BUTYL ESTER (53)

To a solution of (51) (318 mg, 1 mmol) and 2-chloro-quinoline (52) (163mg, 1 mmol) in DMF was added Cs₂CO₃ (650 mg, 2 mmol). The reactionmixture was stirred at 100° C. overnight. The reaction mixture wasdiluted with water, extracted with EtOAc (3×20 mL). The combined organicextracts were washed with water (20 mL) and brine (20 mL), dried overNa₂SO₄ and filtered. The filtrate was evaporated in vacuo and theresidue was purified by flash column chromatography on silica gel togive (53) (346 mg, 0.78 mmol, yield 77.8%).

ESI-MS (M+1): 446 calc. for C₂₆H₃₁N₅O₂ 445.

STEP 5. 2-[3-(3-PIPERIDIN-4-YL-PYRAZIN-2-YL)-AZETIDIN-1-YL]-QUINOLINEHYDROCHLORIDE (54)

A solution of4-[3-(1-quinolin-2-yl-azetidin-3-yl)-pyrazin-2-yl]-piperidine-1-carboxylicacid tert-butyl ester (53) (346 mg, 0.78 mmol) in 4N HCl/MeOH (20 mL)was stirred at RT for 30 min. The reaction mixture was concentrated togive the product (54) (294 mg, 0.77 mmol, yield 98.9%).

ESI-MS (M+1): 346 calc. for C₂₁H₂₃N₅ 345.

Preparation 17

STEP 1. 3-BROMO-5-FLUORO-PYRIDIN-2-YLAMINE (56)

NBS (10 g, 56.2 mmol) was added slowly to a solution of5-fluoro-pyridin-2-ylamine (55) (12.4 g, 56.2 mmol) in MeCN (200 mL).The reaction mixture was stirred at RT overnight. After completion, thesolution was filtered and the filtrate was concentrated to obtain aresidue, which was purified by silica gel chromatography (10% to 20%EtOAc in petroleum ether) to give 3-bromo-5-fluoro-pyridin-2-ylamine(56) (5.2 g, 27.2 mmol, 31% yield) as a yellow solid.

ESI-MS (M+1): 191 calc. for C₅H₄BrFN₂ 190.

STEP 2. 2,3-DIBROMO-5-FLUORO-PYRIDINE (57)

At 60° C., 3-bromo-5-fluoro-pyridin-2-ylamine (56) (1.91 g, 0.01 mol)was dissolved in 48% hydrobromic acid (30 mL). After cooling to −5° C.,bromine (3.24 g, 0.02 mol) was added dropwise over 5 min. A solution ofsodium nitrite (1.01 g, 0.02 mol) in water (3 mL) was then added at arate to keep the temperature of the reaction mixture between −5° C. and0° C. When finished, the temperature was allowed to reach 25° C. Thebromine was reduced with an excess of solid sodium sulfite, and thereaction mixture was extracted with EtOAc (3×50 mL). The combinedorganic extracts were washed with water (30 mL), brine (30 mL), driedover Na₂SO₄ and filtered. The filtrate was evaporated in vacuo and theresidue was purified by flash column chromatography on silica gel (10%to 20% EtOAc in petroleum ether) to give 2,3-dibromo-5-fluoro-pyridine(57) (1.27 g, 5.0 mmol, 50% yield) as a yellow solid.

ESI-MS (M+1): 254 calc. for C₅H₂Br₂FN 253.

STEP 3. 3-(3-BROMO-5-FLUORO-PYRIDIN-2-YL)-AZETIDINE-1-CARBOXYLIC ACIDTERT-BUTYL ESTER (58)

A 100 mL 3-neck round bottom flask fitted with a magnetic stirrer andflushed with nitrogen was charged with zinc dust (813 mg, preactivatedaccording to the above Preparation 1, 12.7 mmol) and DMA (10 mL,anhydrous). 1,2-dibromoethane (236 mg, 1.27 mmol) was added slowly,followed by TMSCl (137 mg, 1.27 mmol). The reaction was stirred for 15min at RT. A solution of N-Boc-3-iodoazetidine (2) (2.7 g, 9.5 mmol) inDMA (10 mL, anhydrous) was added dropwise. The suspension was stirredfor 1 h at RT.

A 100 mL 3-neck round bottom flask fitted with a mechanical stirrer wascharged with 2,3-dibromo-pyridine (57) (1.62 g, 6.4 mmol), Pd(dppf)Cl₂(446 mg, 0.64 mmol, 0.1 eq), cuprous iodide (121 mg, 0.64 mmol), and DMA(20 mL, anhydrous). The dark solution was degassed for 15 min. The clearzinc reagent solution above the residual solid zinc was transferred tothe above 100 mL flask by cannulation. The dark solution was degassedand heated to 80° C. for 16 h. The reaction was diluted with brine andextracted with EtOAc (3×100 mL). The combined organics were washed withwater (2×100 mL) and brine (100 mL), followed by drying over sodiumsulfate. The solution was concentrated and the residue was purified byflash column chromatography (PE:EtOAc=2:1) provided the title compound(58) (860 mg, 2.6 mmol, 40% yield) as a light yellow solid.

ESI-MS (M+1): 331 calc. for C₁₃H₁₆BrFN₂O₂ 330.

Preparation 18

STEP 1. [1-(3,6-DICHLORO-PYRIDAZIN-4-YL)-PIPERIDIN-4-YL]-METHANOL (60)

To a solution of 3,4,6-trichloro-pyridazine (59) (364 mg, 2 mmol) andpiperidin-4-yl-methanol (35) (253 mg, 2.2 mmol) in DMSO (5 mL) was addedEt₃N (404 mg, 4 mmol). The reaction mixture was stirred at 100° C.overnight. The reaction mixture was diluted with water, extracted withEtOAc (30 mL×3). The combined organic extracts were washed with water(30 mL) and brine (30 mL), dried over Na₂SO₄ and filtered. The filtratewas evaporated in vacuo and the residue was purified by flash columnchromatography on silica gel to give[1-(3,6-dichloro-pyridazin-4-yl)-piperidin-4-yl]-methanol (60) (292.3mg, 1.12 mmol, yield 75.99%).

ESI-MS (M+1): 262 calc. for C₁₀H₁₃Cl₂N₃O 261.

STEP 2.4-[4-(TERT-BUTYL-DIMETHYL-SILANYLOXYMETHYL)-PIPERIDIN-1-YL]-3,6-DICHLORO-PYRIDAZINE(61)

[1-(3,6-dichloro-pyridazin-4-yl)-piperidin-4-yl]-methanol (60) (1.83 g,7 mol) upon treatment with TBSCl (2.1 g, 14 mmol) and imidazole (2.38 g,35 mmol) in DMF (15 mL) stirred at RT for 3 h, The reaction mixture wasdiluted with water, extracted with EtOAc (40 mL×3). The combined organicextracts were washed with water (20 mL) and brine (20 mL), dried overNa₂SO₄ and filtered. The filtrate was evaporated in vacuo and theresidue was purified by flash column chromatography on silica gel togive4-[4-(tert-butyl-dimethyl-silanyloxymethyl)-piperidin-1-yl]-3,6-dichloro-pyridazine(61) (2.55 g, 6.8 mmol, 99% yield)

ESI-MS (M+1): 376 calc. for C₁₆H₂₇Cl₂N₃OSi 375.

STEP 3.3-{4-[4-(TERT-BUTYL-DIMETHYL-SILANYLOXYMETHYL)-PIPERIDIN-1-YL]-6-CHLORO-PYRIDAZIN-3-YL}-AZETIDINE-1-CARBOXYLICACID TERT-BUTYL ESTER (62)

A 100 mL 3-neck round bottom flask fitted with a magnetic stirrer andflushed with nitrogen was charged with zinc dust (813 mg, preactivatedaccording to the above Preparation 1, 12.7 mmol) and DMA (10 mL,anhydrous). 1,2-dibromoethane (236 mg, 1.27 mmol) was added slowly,followed by TMSCl (137 mg, 1.27 mmol). The reaction was stirred for 15min at RT. A solution of N-Boc-3-iodoazetidine (2) (2.7 g, 9.5 mmol) inDMA (10 mL, anhydrous) was added dropwise. The suspension was stirredfor 1 h at RT.

A 100 mL 3-neck round bottom flask fitted with a mechanical stirrer wascharged with4-[4-(tert-butyl-dimethyl-silanyloxymethyl)-piperidin-1-yl]-3,6-dichloro-pyridazine(61) (2.4 g, 6.4 mmol), Pd(dppf)Cl₂ (446 mg, 0.64 mmol), cuprous iodide(121 mg, 0.64 mmol), and DMA (20 mL, anhydrous). The dark solution wasdegassed for 15 min. The clear zinc reagent solution above the residualsolid zinc was transferred to the above 100 mL flask by cannulation. Thedark solution was degassed and heated to 80° C. for 16 h. The reactionwas diluted with brine and extracted with EtOAc (3×100 mL). The combinedorganics were washed with water (2×100 mL) and brine (100 mL), followedby drying over sodium sulfate. The solution was concentrated and theresidue was purified by flash column chromatography (PE:EAOAc=2:1)provides the title compound (62) (1.25 g, 2.5 mmol, 39% yield) as alight yellow solid.

ESI-MS (M+1): 497 calc. for C₂₄H₄₁ClN₄O₃Si 496.

STEP 4.3-{4-[4-(TERT-BUTYL-DIMETHYL-SILANYLOXYMETHYL)-PIPERIDIN-1-YL]-PYRIDAZIN-3-YL}-AZETIDINE-1-CARBOXYLICACID TERT-BUTYL ESTER (63)

To a solution of3-{4-[4-(tert-butyl-dimethyl-silanyloxymethyl)-piperidin-1-yl]-6-chloro-pyridazin-3-yl}-azetidine-1-carboxylicacid tert-butyl ester (62) (843 mg, 1.7 mmol) in MeOH was added Pd/C(10%, 0.5 g) under nitrogen. The reaction was stirred under hydrogen atRT for 6 h, filtered to remove Pd/C and concentrated to dryness to give3-{4-[4-(tert-butyl-dimethyl-silanyloxymethyl)-piperidin-1-yl]-pyridazin-3-yl}-azetidine-1-carboxylicacid tert-butyl ester (63) (730 mg, 1.58 mmol yield 92.9%).

ESI-MS (M+1): 463 calc. for C₂₄H₄₂N₄O₃Si 462.

STEP 5. [1-(3-AZETIDIN-3-YL-PYRIDAZIN-4-YL)-PIPERIDIN-4-YL]-METHANOLHYDROCHLORIDE (64)

A mixture of3-{4-[4-(tert-butyl-dimethyl-silanyloxymethyl)-piperidin-1-yl]-pyridazin-3-yl}-azetidine-1-carboxylicacid tert-butyl ester (63) (730 mg, 1.58 mmol) in 4 M HCl/MeOH solution(20 mL) was stirred at RT for 30 min. Then the solvent was evaporated at40° C. to give[1-(3-azetidin-3-yl-pyridazin-4-yl)-piperidin-4-yl]-methanolhydrochloride (64) (387 mg, 1.56 mmol, 98% yield) as a yellow solid.

ESI-MS (M+1): 249 calc. for C₁₃H₂₀N₄O 248.

Preparation 19

STEP 1. 4-DIMETHYLCARBAMOYL-PIPERIDINE-1-CARBOXYLIC ACID TERT-BUTYLESTER (66)

To a mixture of piperidine-1,4-dicarboxylic acid mono-tert-butyl ester(65) (229 mg, 1 mmol, AalenChem) in DCM (5 mL) was added TEA (202 mg, 2mmol) and HATU (414 mg, 1.2 mmol). The reaction mixture was stirred for5 min and dimethylamine hydrochloride (81 mg, 1 mmol) was added. Thereaction mixture was stirred at RT overnight. The mixture was dilutedwith water (10 mL), and extracted with EtOAc (2×20 mL). The combinedorganic extracts were washed with water (5 mL) and brine (5 mL), driedover Na₂SO₄, and filtered. The filtrate was evaporated in vacuo and theresidue was purified by column chromatography to give4-dimethylcarbamoyl-piperidine-1-carboxylic acid tert-butyl ester (66)(220 mg, 0.85 mmol, 85% yield) as a light yellow oil.

STEP 2. PIPERIDINE-4-CARBOXYLIC ACID DIMETHYLAMIDE HYDROCHLORIDE (67)

A solution of 4-dimethylcarbamoyl-piperidine-1-carboxylic acidtert-butyl ester (66) (220 mg, 0.85 mmol) in 4N HCl/MeOH (20 mL) wasstirred at RT for 30 min. The reaction mixture was concentrated to givethe product piperidine-4-carboxylic acid dimethylamide hydrochloride(67) (163 mg, 0.85 mmol, yield 99.9%).

ELSD-MS (M+1): 157 calc. for C₈H₁₆N₂O 156.

The following Table 5 lists compounds of Preparation P19.1 to P19.4,which were made analogous to Preparation 19 by using the appropriatematerials.

TABLE 5 PREPARATION P19.1 TO P19.4 ESI- MS Chemical (M + Ex. # ChemicalStructure Name 1) P19.1

4-Dimethyl- carbamoyl- piperidine-1- carboxylic acid tert- butyl ester257 P19.2

4-methyl- carbamoyl- piperidine-1- carboxylic acid tert- butyl ester 243P19.3

Piperidine- 4-carboxylic acid dimethyl- amide hydro- chloride 157 P19.4

Piperidine-4- carboxylic acid methyl- amide hydro- chloride 143

Preparation 20

STEP 1. 3-(3-M-TOLYL-QUINOXALIN-2-YL)-AZETIDINE-1-CARBOXYLIC ACIDTERT-BUTYL ESTER

To a solution of 3-(3-chloro-quinoxalin-2-yl)-azetidine-1-carboxylicacid tert-butyl ester (46) (639 mg, 2.0 mmol, as prepared in the abovePreparation 14), 3-methyl-phenylboronic acid (68) (299.2 mg, 2.2 mmol),K₃PO₄ (818 mg, 4.0 mmol) in dioxane (20 mL) and water (4 mL) was addedPd(dppf)Cl₂ (73.2 mg, 0.1 mmol) then the reaction mixture was stirred at90° C. under nitrogen atmosphere overnight. The reaction mixture wasfiltered through CELITE® and washed with EtOAc (50 mL). The filtrate wasconcentrated and the crude product was purified by silica gel column togive 3-(3-m-tolyl-quinoxalin-2-yl)-azetidine-1-carboxylic acidtert-butyl ester (69) (637 mg, 1.7 mmol, yield 85%).

ESI-MS (M+1): 376 calc. for C₂₃H₂₅N₃O₂ 375.

STEP 2. 2-AZETIDIN-3-YL-3-M-TOLYL-QUINOXALINE HYDROCHLORIDE (70)

A solution of 3-(3-m-tolyl-quinoxalin-2-yl)-azetidine-1-carboxylic acidtert-butyl ester (69) (637 mg, 1.7 mmol) in 4N HCl/MeOH (25 mL) wasstirred at RT for 30 min. The reaction mixture was concentrated to give2-azetidin-3-yl-3-m-tolyl-quinoxaline hydrochloride (70) (523 mg, 1.68mmol, yield 98.8%).

ESI-MS (M+1): 276 calc. for C₁₈H₁₇N₃ 275.

The following Table 6 lists compounds of Preparation P20.1 to P20.10,which were made analogous to Preparation 20 by using the appropriatematerials.

TABLE 6 PREPARATION P20.1 TO P20.10 Ex. # Chemical Structure ChemicalName ESI-MS (M + 1) P20.1

3-(3-m-Tolyl-quinoxalin-2-yl)- azetidine-1-carboxylic acid tert- butylester 376 P20.2

tert-butyl 3-(3-(4- aminophenyl)quinoxalin-2- yl)azetidine-1-carboxylic376 P20.3

tert-butyl 3-(3-(3- hydroxyphenyl)quinoxalin-2-yl)azetidine-1-carboxylate 378 P20.4

tert-butyl 3-(3-(3- methoxyphenyl)quinoxalin-2-yl)azetidine-1-carboxylate 392 P20.5

tert-butyl 3-(3- phenylquinoxalin-2- yl)azetidine-1-carboxylate 362P20.6

2-Azetidin-3-yl-3-m-tolyl- quinoxaline hydrochloride 276 P20.7

4-(3-(azetidin-3-yl)quinoxalin- 2-yl)aniline hydrochloride 277 P20.8

3-(3-(azetidin-3-yl)quinoxalin- 2-yl)phenol hydrochloride 278 P20.9

2-(azetidin-3-yl)-3-(3- methoxyphenyl)quinoxaline hydrochloride 292P20.10

2-(azetidin-3-yl)-3- phenylquinoxaline hydrochloride 262

Preparation 21

STEP 1. 3-[3-(2-HYDROXY-PHENYL)-PYRAZIN-2-YL]-AZETIDINE-1-CARBOXYLICACID TERT-BUTYL ESTER (72)

To a solution of 3-(3-chloro-pyrazin-2-yl)-azetidine-1-carboxylic acidtert-butyl ester (7) (540 mg, 2.0 mmol, see Preparation 2),2-hydroxy-phenylboronic acid (71) (303.6 mg, 2.2 mmol), K₃PO₄ (818 mg,4.0 mmol), in dioxane (20 mL) and water (4 mL) was added Pd(dppf)Cl₂(73.2 mg, 0.1 mmol) then the reaction mixture was stirred at 90° C.under nitrogen atmosphere overnight. The reaction mixture was filteredthrough CELITE® and washed with EtOAc (50 mL). The filtrate wasconcentrated and the crude product was purified by silica gel column togive (72) (601.7 mg, 1.84 mmol, yield 91.85%).

ESI-MS (M+1): 328 calc. for C₁₈H₂₁N₃O₃ 327.

STEP 2. 2-(3-AZETIDIN-3-YL-PYRAZIN-2-YL)-PHENOL HYDROCHLORIDE (73)

A solution of3-[3-(2-hydroxy-phenyl)-pyrazin-2-yl]-azetidine-1-carboxylic acidtert-butyl ester (72) (325 mg, 1.0 mmol) in 4N HCl/MeOH (20 mL) wasstirred at RT for 30 min. The reaction mixture was concentrated to give(74) (274.3 mg, 0.99 mmol, yield 99.24%).

ESI-MS (M+1): 228 calc. for C₁₃H₁₃N₃O 227.

The following Table 7 lists compounds of Preparation P21.1 to P21.8,which were made analogous to Preparation 21 by using the appropriatematerials.

TABLE 7 PREPARATION P21.1 TO P21.8 Chemical ESI-MS Ex. # ChemicalStructure Name (M + 1) P21.1

2-(3-azetidin-3-yl) pyrazin-2- yl)phenol hydrochloride 228 P21.2

3-(3-(azetidin-3- yl)pyrazin-2- yl)phenol hydrochloride 228 P21.3

4-(3-(azetidin-3- yl)pyrazin-2- yl)phenol hydrochloride 228 P21.4

2-(3-(azetidin-3- yl)-pyrazin-2- yl)aniline hydrochloride 226 P21.5

3-(3-(azetidin-3- yl)pyrazin-2- yl)aniline hydrochloride 226 P21.6

4-(3-(azetidin-3- yl)pyrazin-2- yl)aniline hydrochloride 226 P21.7

2-(azetidin-3- yl)-3-(4-fluoro-3- methoxyphenyl) pyrazine hydrochloride260 P21.8

4-(3-(azetidin-3- yl)pyrazin-2- yl)-2- fluoroaniline hydrochloride 245

Preparation 22

STEP 1. TERT-BUTYL3-(3-(PIPERIDIN-1-YL)PYRAZIN-2-YL)AZETIDINE-1-CARBOXYLATE (74)

To a solution of 3-(3-chloro-pyrazin-2-yl)-azetidine-1-carboxylic acidtert-butyl ester (7) (200 mg, 0.74 mmol, see Preparation 2) andpiperidine (69.2 mg, 0.84 mmol) in DMSO (5 mL) was added Et₃N (149.5 mg,1.48 mmol). The reaction mixture was stirred at 100° C. overnight. Thereaction mixture was diluted with water, extracted with EtOAc (30 mL×3).The combined organic extracts were washed with water (30 mL) and brine(30 mL), dried over Na₂SO₄ and filtered. The filtrate was evaporated invacuo and the residue was purified by flash column chromatography onsilica gel to give tert-butyl3-(3-(piperidin-1-yl)pyrazin-2-yl)azetidine-1-carboxylate (74). (194 mg,0.56 mmol, yield 75.99%).

STEP 2. 2-AZETIDIN-3-YL-3-PIPERIDIN-1-YL-PYRAZINE HYDROCHLORIDE (75)

A solution of 3-(3-piperidin-1-yl-pyrazin-2-yl)-azetidine-1-carboxylicacid tert-butyl ester (74) (191 mg, 0.6 mmol) in 4N HCl/MeOH (13 mL) wasstirred at RT for 30 min. The reaction mixture was concentrated to give(75) (150 mg, 0.59 mmol, yield 99%). ESI-MS (M+1): 219 calc. forC₁₂H₁₈N₄ 218

The following Table 8 lists compounds of Preparation P22.1 to P22.12,which were made analogous to Preparation 22 by using the appropriatematerials.

TABLE 8 PREPARATION P22.1 TO P22.12 ESI- MS Chemical (M + Ex. # ChemicalStructure Name 1) P22.1

tert-butyl 3- (3-(piperidin-1- yl)pyrazin-2- yl)azetidine-1- carboxylate319 P22.2

tert-butyl 3- (3-(4- methyl- piperidin- 1-yl)pyrazin- 2-yl)azetidine-1-carboxylate 333 P22.3

tert-butyl 3- (3-(4- carbamoyl- piperidin-1- yl)pyrazin-2-yl)azetidine-1- carboxylate 362 P22.4

tert-butyl 3- (3-(4- (dimethyl- carbamoyl) piperidin- 1-yl)pyrazin-2-yl)azetidine-1- carboxylate 390 P22.5

tert-butyl 3- (3-(4- (methyl- carbamoyl) piperidin-1- yl)pyrazin-2-yl)azetidine-1- carboxylate 376 P22.6

tert-butyl 3- (3-(4- acetylpiperazin- 1-yl)pyrazin-2- yl)azetidine-1-carboxylate 362 P22.7

2-(azetidin-3- yl)-3-(piperidin- 1-yl)pyrazine hydrochloride 219 P22.8

2-(azetidin-3- yl)-3-(4- methylpiperidin- 1-yl)pyrazine hydrochloride233 P22.9

1-(3-(azetidin-3- yl)pyrazin-2- yl)piperidine- 4-carboxamidehydrochloride 262 P22.10

1-(3-(azetidin-3- yl)pyrazin-2- yl)-N,N- dimethyl- piperidine-4-carboxamide hydrochloride 290 P22.11

1-(3-(azetidin- 3-yl)pyrazin-2- yl)-N-methyl- piperidine-4- carboxamidehydrochloride 276 P22.12

1-(4-(3-(azetidin- 3-yl)pyrazin- 2-yl)piperazin- 1-yl)ethanonehydrochloride 262

Preparation 23

STEP 1.3-(5′-FLUORO-4-HYDROXYMETHYL-3,4,5,6-TETRAHYDRO-2H-[1,3′]BIPYRIDINYL-2′-YL)-AZETIDINE-1-CARBOXYLICACID TERT-BUTYL ESTER (76)

To a solution of3-(3-bromo-5-fluoro-pyridin-2-yl)-azetidine-1-carboxylic acid tert-butylester (58) (660 mg, 2 mmol, Preparation 17) and piperidin-4-yl-methanol(35) (230 mg, 2 mmol) in DMSO (20 mL) was added Et₃N (404 mg, 4 mmol).The reaction mixture was stirred at 100° C. overnight. The reactionmixture was diluted with water, extracted with EtOAc (50 mL×3). Thecombined organic extracts were washed with water (30 mL) and brine (30mL), dried over Na₂SO₄ and filtered. The filtrate was evaporated invacuo and the residue was purified by flash column chromatography(EtOAc:PE=3:1) on silica gel to give (76) (490 mg, 1.34 mmol, yield67%). ESI-MS (M+1): 366 calc. for C₁₉H₂₈FN₃O₃ 365.

STEP 2.(2′-AZETIDIN-3-YL-5′-FLUORO-3,4,5,6-TETRAHYDRO-2H-[1,3′]BIPYRIDINYL-4-YL)-METHANOLHYDROCHLORIDE (77)

A mixture of3-(5′-fluoro-4-hydroxymethyl-3,4,5,6-tetrahydro-2H-[1,3]bipyridinyl-2′-yl)-azetidine-1-carboxylicacid tert-butyl ester (76) (490 mg, 1.34 mmol) in 4 M HCl/MeOH solution(10 mL) was stirred at RT for 30 min. Then the solvent was evaporated at40° C. to give (77) (392 mg, 1.3 mmol, 98% yield) as a yellow solid.ESI-MS (M+1): 266 calc. for C₁₄H₂₀FN₃O 265.

Preparation 24

STEP 1. 3-(3-BROMO-PYRIDIN-2-YL)-AZETIDINE-1-CARBOXYLIC ACID TERT-BUTYLESTER (3)

A 100 mL 3-neck round bottom flask fitted with a magnetic stirrer andflushed with nitrogen was charged with zinc dust (813 mg, preactivatedaccording to the above Preparation 1, 12.7 mmol, 2.0 eq.) and DMA (10mL, anhydrous). 1,2-Dibromoethane (236 mg, 1.27 mmol, 0.2 eq) was addedslowly, followed by TMSCl (137 mg, 1.27 mmol, 0.2 eq). The reaction wasstirred for 15 min at RT. A solution of N-Boc-3-iodoazetidine (2) (2.7g, 9.5 mmol, 1.5 eq) in DMA (10 mL, anhydrous) was added dropwise. Thesuspension was stirred for 1 h at RT.

A 100 mL 3-neck round bottom flask fitted with a mechanical stirrer wascharged with 2,3-dibromo-pyridine (1) (1.5 g, 6.4 mmol, 1.0 eq),PdCl₂(dppf) (446 mg, 0.64 mmol, 0.1 eq), CuI (121 mg, 0.64 mmol, 0.1eq), and DMA (20 mL, anhydrous). The dark solution was degassed for 15min. The clear zinc reagent solution above the residual solid zinc wastransferred to the above 100 mL flask by cannulation. The dark solutionwas degassed and heated to 80° C. for 16 h. The reaction was dilutedwith brine and extracted with EtOAc (3×100 mL). The combined organicswere washed with water (2×100 mL) and brine (100 mL), followed by dryingover sodium sulfate. The solution was concentrated and the residue waspurified by flash column chromatography (PE:EtOAc=2:1) provides thetitle compound (3) (600 mg, 31% yield) as a light yellow solid.

ESI-MS (M+1): 313 calc. for C₁₃H₁₇BrN₂O₂ 312.

STEP 2. 3-(3-PHENYL-PYRIDIN-2-YL)-AZETIDINE-1-CARBOXYLIC ACID TERT-BUTYLESTER (79)

To a stirred solution of 3-(3-bromo-pyridin-2-yl)-azetidine-1-carboxylicacid tert-butyl ester (3) (150 mg, 0.48 mmol) in dioxane (10 mL) wasadded phenylboronic acid (78) (87 mg, 0.71 mmol), Na₂CO₃ (152 mg, 1.4mmol) and H₂O (2 mL). The reaction mixture was degassed with N₂ and thenPdCl₂(dppf) (35 mg, 0.05 mmol) was added. The reaction mixture wasstirred at 80° C. for 12 h. The reaction mixture was left to reach RTand filtered through a pad of CELITE® and the filter cake was washedwith CH₂Cl₂ (20 mL×3). The combined filtrates were evaporated in vacuoand the residue was purified by column chromatography ((EtOAc:Petrolether=3:1) to give the desired compound (79) (130 mg, 87% yield). ESI-MS(M+1): 311 calc. for C₁₉H₂₂N₂O₂ 310.

STEP 3. 2-AZETIDIN-3-YL-3-PHENYL-PYRIDINE HYDROCHLORIDE

A mixture of 3-(3-phenyl-pyridin-2-yl)-azetidine-1-carboxylic acidtert-butyl ester (79) (130 mg, 0.60 mmol) in HCl/MeOH solution (5 mL)was stirred at RT for 30 min. Then the solvent was evaporated at 40° C.to give 2-Azetidin-3-yl-3-phenyl-pyridine hydrochloride (80) (100 mg,100% yield) as a yellow solid.

ESI-MS (M+1): 211 calc. for C₁₄H₁₄N₂ 210.

Preparation 25

STEP 1. 1-METHYL-1H-BENZOIMIDAZOLE-2-CARBOXYLIC ACID METHYL ESTER (81)

To a solution of 1H-benzoimidazole-2-carboxylic acid methyl ester (18)(177 mg, 1.0 mmol) in dry DMF (5 mL) was added sodium hydride (appliedas 60% dispersion in oil, 62 mg, 1.5 mmol)) at 0° C. under N₂atmosphere. After 0.5 h, iodomethane (284 mg, 2.0 mmol) was addedslowly. The reaction mixture was stirred at RT for 4 h. The reaction wasdiluted with brine at 0° C. and extracted with EtOAc (3×20 mL). Thecombined organics were washed with water (2×15 mL), brine (20 mL), driedover sodium sulfate and filtered. The filtrate was concentrated andpurified by flash column chromatography to provide the title compound(81) (180 mg, 90% yield) as a light yellow solid.

ESI-MS (M+1): 191 calc. for C10H10N2O2 190.

STEP 2. 1-METHYL-1H-BENZOIMIDAZOLE-2-CARBOXYLIC ACID (82)

A mixture of 1-methyl-1H-benzoimidazole-2-carboxylic acid methyl ester(81) (190 mg, 1.0 mmol) and NaOH (80 mg, 2.0 mmol) in MeOH /H₂O (1:1, 20mL) was stirred at 50° C. for 1 h. The mixture was concentrated, thendiluted with water (15 mL), adjusted pH=2 with concentrated HCl. Thenthe precipitate was formed and filtered, washed with water and dried togive 1-methyl-1H-benzoimidazole-2-carboxylic acid (82) (176 mg, 1.0mmol, yield 100%)

ESI-MS (M+1): 177 calc. for C₉H₈N₂O₂ 176.

STEP 3.[3-(3-CHLORO-PYRAZIN-2-YL)-AZETIDIN-1-YL]-(1-METHYL-1H-BENZOIMIDAZOL-2-YL)-METHANONE(83)

A mixture of 1-methyl-1H-benzoimidazole-2-carboxylic acid (82) (176 mg,1.0 mmol), 2-Azetidin-3-yl-3-chloro-pyrazine hydrochloride (8) (169 mg,1.0 mmol), HOBt (151 mg, 1.2 mmol), EDCI (231 mg, 1.2 mmol) andN-methyl-morpholine (NMM) (300 mg, 3.0 mmol) in DMF (5 mL) was stirredat RT for 24 h. The mixture was diluted with water (20 mL), andfiltered. The filter cake was washed with water and dried in vacuo toprovide[3-(3-chloro-pyrazin-2-yl)-azetidin-1-yl]-(1-methyl-1H-benzoimidazol-2-yl)-methanone(83) (300 mg, yield 90%).

ESI-MS (M+1): 328 calc. for C₁₆H₁₄ClN₅O 327.

Preparation 26

[3-(3-CHLORO-PYRAZIN-2-YL)-AZETIDIN-1-YL]-[1-(2,2,2-TRIFLUORO-ETHYL)-1H-BENZOIMIDAZOL-2-YL]-METHANONE(85)

To a solution of(1H-benzoimidazol-2-yl)-[3-(3-chloro-pyrazin-2-yl)-azetidin-1-yl]-methanone(84), as prepared in Preparation 36 below, (314 mg, 1.0 mmol) in dry DMF(10 mL) was added sodium hydride (applied as 60% dispersion in oil, 62mg, 1.5 mmol)) at 0° C. under N₂ atmosphere. After 0.5 h,1,1,1-Trifluoro-2-iodo-ethane (418 mg, 2.0 mmol) was added slowly. Thereaction mixture was stirred at RT for 4 h. The reaction was quenchedwith water (10 mL) at 0° C. and extracted with EtOAc (3×20 mL). Thecombined organics were washed with water (2×15 mL), brine (20 mL), driedover sodium sulfate and filtered. The filtrate was concentrated and theresidue was purified by flash column chromatography to provide (85) (355mg, 0.90 mmol, 90% yield) as white solid.

ESI-MS (M+1): 396 calc. for C₁₇H₁₃ClF₃N₅O 395.

Preparation 27

STEP 1. 3-(3-PHENYL-PYRIDIN-2-YL)-AZETIDINE-1-CARBOXYLIC ACID TERT-BUTYLESTER (86)

To a stirred solution of 3-(3-bromo-pyridin-2-yl)-azetidine-1-carboxylicacid tert-butyl ester (3) (158 mg, 0.48 mmol) in dioxane (10 mL) wasadded phenylboronic acid (78) (87 mg, 0.71 mmol), Na₂CO₃ (152 mg, 1.4mmol) and H₂O (2 mL). The reaction mixture was degassed with N₂ and thenPdCl₂(dppf) (35 mg, 0.05 mmol) was added. The reaction mixture wasstirred at 80° C. for 12 h. The reaction mixture was left to reach RTand filtered through a pad of CELITE® and the filter cake was washedwith CH₂Cl₂ (20 mL×3). The combined filtrates were evaporated in vacuoand the residue was purified by column chromatography ((EtOAc:Petrolether=3:1) to give 3-(3-phenyl-pyridin-2-yl)-azetidine-1-carboxylic acidtert-butyl ester (125 mg, 0.38 mmol, 80% yield).

ESI-MS (M+1): 329 calc. for C₁₉H₂₁FN₂O₂ 328.

STEP 2. 2-AZETIDIN-3-YL-5-FLUORO-3-PHENYL-PYRIDINE HYDROCHLORIDE (87)

A mixture of 3-(3-phenyl-pyridin-2-yl)-azetidine-1-carboxylic acidtert-butyl ester (86) (125 mg, 0.38 mmol) in 4 M HCl/MeOH solution (10mL) was stirred at RT for 30 min. Then the solvent was evaporated at 40°C. to give 2-azetidin-3-yl-5-fluoro-3-phenyl-pyridine hydrochloride (87)(100 mg, 0.38 mmol, 100% yield) as a yellow solid.

ESI-MS (M+1): 229 calc. for C₁₄H₁₃FN₂ 228.

Preparation 28

STEP 1. 4-(3-CHLORO-PYRAZIN-2-YL)-PIPERIDINE-1-CARBOXYLIC ACIDTERT-BUTYL ESTER (88)

A 100 mL 3-neck round bottom flask fitted with a magnetic stirrer andflushed with nitrogen was charged with zinc dust (813 mg, preactivatedaccording to the above Preparation 1, 12.7 mmol, 2.0 eq.) and DMA (10mL, anhydrous). 1,2-dibromoethane (236 mg, 1.27 mmol, 0.2 eq) was addedslowly, followed by TMSCl (137 mg, 1.27 mmol, 0.2 eq). The reaction wasstirred for 15 min at RT. A solution of 4-iodo-piperidine-1-carboxylicacid tert-butyl ester (38) (2.95 g, 9.5 mmol, 1.5 eq) in DMA (10 mL,anhydrous) was added dropwise. The suspension was stirred for 1 h at RT.

A 100 mL 3-neck round bottom flask fitted with a mechanical stirrer wascharged with 2,3-dichloro-pyrazine (6) (0.95 g, 6.4 mmol, 1.0 eq),PdCl₂(dppf) (446 mg, 0.64 mmol, 0.1 eq), CuI (121 mg, 0.64 mmol, 0.1eq), and DMA (20 mL, anhydrous). The dark solution was degassed for 15min. The clear zinc reagent solution above the residual solid zinc wastransferred to the above 100 mL flask by cannulation. The dark solutionwas degassed and heated to 80° C. for 16 h. The reaction was dilutedwith brine and extracted with EtOAc (3×100 mL). The combined organicswere washed with water (2×100 mL) and brine (100 mL), followed by dryingover sodium sulfate. The solution was concentrated and the residue waspurified by flash column chromatography (PE:EA=2:1) provides the titlecompound (88) (0.95 g, 3.2 mmol, 50% yield) as a light yellow solid.

ESI-MS (M+1): 298 calc. for C₁₄H₂₀ClN₃O₂ 297.

STEP 4. 4-(3-PHENYL-PYRAZIN-2-YL)-PIPERIDINE-1-CARBOXYLIC ACIDTERT-BUTYL ESTER (89)

To a stirred solution of (88) (142 mg, 0.48 mmol) in dioxane (10 mL) wasadded phenylboronic acid (78) (87 mg, 0.71 mmol), Na₂CO₃ (152 mg, 1.4mmol) and H₂O (2 mL). The reaction mixture was degassed with N₂ and thenPdCl₂(dppf) (35 mg, 0.05 mmol) was added. The reaction mixture wasstirred at 80° C. for 12 h. The reaction mixture was left to reach RTand filtered through a pad of CELITE® and the filter cake was washedwith CH₂Cl₂ (20 mL×3). The combined filtrates were evaporated in vacuoand the residue was purified by column chromatography ((EtOAc:Petrolether=1:1) to give 4-(3-Phenyl-pyrazin-2-yl)-piperidine-1-carboxylicacid tert-butyl ester (89) (128 mg, 0.38 mmol, 80% yield).

ESI-MS (M+1): 340 calc. for C₂₀H₂₅N₃O₂ 339.

STEP 4. 2-PHENYL-3-PIPERIDIN-4-YL-PYRAZINE HYDROCHLORIDE (90)

A mixture of 4-(3-Phenyl-pyrazin-2-yl)-piperidine-1-carboxylic acidtert-butyl ester (89) (128 mg, 0.38 mmol) in 4 M HCl/MeOH solution (10mL) was stirred at RT. for 30 min. Then the solvent was evaporated at40° C. to give 2-phenyl-3-piperidin-4-yl-pyrazine hydrochloride (90)(105 mg, 0.38 mmol, 100% yield) as a yellow solid.

ESI-MS (M+1): 240 calc. for C₁₅H₁₇N₃ 239.

Preparation 29

STEP 1. 3-(3-CHLORO-QUINOXALIN-2-YL)-AZETIDINE-1-CARBOXYLIC ACIDTERT-BUTYL ESTER (91)

A 100 mL 3-neck round bottom flask fitted with a magnetic stirrer andflushed with nitrogen was charged with zinc dust (1.3 g, preactivatedaccording to the above Preparation 1, 20 mmol, 2.0 eq.) and DMA (10 mL,anhydrous). 1,2-dibromoethane (400 mg, 2.0 mmol, 0.2 eq) was addedslowly, followed by TMSCl (240 mg, 2.0 mmol, 0.2 eq). The reaction wasstirred for 15 min at RT. A solution of N-Boc-3-iodoazetidine (2) (4 g,16 mmol, 1.6 eq) in DMA (10 mL, anhydrous) was added dropwise. Thesuspension was stirred for 1 h at RT.

A 100 mL 3-neck round bottom flask fitted with a mechanical stirrer wascharged with 2,3-Dichloro-quinoxaline (44) (2 g, 10 mmol, 1.0 eq),PdCl₂(dppf) (800 mg, 1.0 mmol, 0.1 eq), CuI (200 mg, 1.0 mmol, 0.1 eq),and DMA (20 mL, anhydrous). The dark solution was degassed for 15 min.The clear zinc reagent solution above the residual solid zinc wastransferred to the above 100 mL flask by cannulation. The dark solutionwas degassed and heated to 80° C. for 16 h. The reaction was dilutedwith brine and extracted with EtOAc (3×100 mL). The combined organicswere washed with water (2×100 mL) and brine (100 mL), followed by dryingover sodium sulfate. The solution was concentrated and the residue waspurified by flash column chromatography (PE:EA=2:1) provides3-(3-Chloro-quinoxalin-2-yl)-azetidine-1-carboxylic acid tert-butylester (91) (1.43 g, 4.5 mmol, 45% yield) as a light yellow solid.

ESI-MS (M+1): 320 calc. for C₁₆H₁₈ClN₃O₂ 319.

STEP 2. 3-(3-PIPERIDIN-1-YL-QUINOXALIN-2-YL)-AZETIDINE-1-CARBOXYLIC ACIDTERT-BUTYL ESTER (92)

To a mixture of 3-(3-chloro-quinoxalin-2-yl)-azetidine-1-carboxylic acidtert-butyl ester (91) (0.16 g, 0.50 mmol) and piperidine (0.085 g, 1.0mmol) was added triethylamine (0.10 g, 1.0 mmol) and DMSO (3 mL). Thesolution was heated to 160° C. in microwave for 2 h. Then the mixturewas diluted with water (10 mL) and extracted with EtOAc (2×20 mL). Thecombined organic extracts were washed with water (10 mL) and brine (10mL), dried over Na₂SO₄ and filtered. The filtrate was evaporated invacuo and the residue was purified by flash column chromatography onsilica gel (20% to 50% EtOAc in petroleum ether) to give3-(3-piperidin-1-yl-quinoxalin-2-yl)-azetidine-1-carboxylic acidtert-butyl ester (92) (0.16 g, 0.90 mmol, 90% yield) as a white solid.ESI-MS (M+1): 369 calc. for C₂₁H₂₈N₄O₂ 368.

STEP 3. 2-AZETIDIN-3-YL-3-PIPERIDIN-1-YL-QUINOXALINE HYDROCHLORIDE (93)

A mixture of 3-(3-piperidin-1-yl-quinoxalin-2-yl)-azetidine-1-carboxylicacid tert-butyl ester (92) (139 mg, 0.38 mmol) in 4 M HCl/MeOH solution(10 mL) was stirred at RT for 30 min. Then the solvent was evaporated at40° C. to give 2-azetidin-3-yl-3-piperidin-1-yl-quinoxalinehydrochloride (93) (115 mg, 0.38 mmol, 100% yield) as a yellow solid.ESI-MS (M+1): 269 calc. for C₁₆H₂₀N₄ 269

The following Table 9 lists compounds of Preparation P29.1 to P29.4,which were made analogous to Preparation 29 by using the appropriatematerials.

TABLE 9 PREPARATION P29.1 TO P29.4 Ex. # Structure Chemical Name ESI-MS(M + 1) P29.1

3-(3-Piperidin-1-yl-quinoxalin-2-yl)- azetidine-1-carboxylic acidtert-butyl ester 369 P29.2

tert-butyl 3-(3-(4-hydroxypiperidin-1- yl)quinoxalin-2-yl)azetidine-1-carboxylate 385 P29.3

2-Azetidin-3-yl-3-piperidin-1-yl- quinoxaline hydrochloride 269 P29.4

1-(3-(azetidin-3-yl)quinoxalin-2- yl)piperidin-4-ol hydrochloride 285

Preparation 30

STEP 1.3-(2,3-DIHYDRO-INDOL-1-YL)-3′,4′,5′,6′-TETRAHYDRO-2′H-[2,4′]BIPYRIDINYL-1′-CARBOXYLICACID TERT-BUTYL ESTER (95)

A mixture of3-bromo-3′,4′,5′,6′-tetrahydro-2′H-[2,4′]bipyridinyl-1′-carboxylic acidtert-butyl ester (94) (280 mg, 0.82 mmol), 2,3-dihydro-1H-indole (97 mg,0.82 mmol), Pd₂(dba)₃ (37 mg, 0.04 mmol), BINAP (24 mg, 0.04 mmol) andt-BuONa (173 mg, 1.64 mmol) in toluene (20 mL) was stirred at 100° C.for 12 h. The mixture was left to reach RT and filtered through a pad ofCelite and the filter cake was washed with CH₂Cl₂ (30 mL). The combinefiltrate was evaporated in vacuo and the residue was purified by flashcolumn chromatography (20% to 40% EtOAc in petroleum ether) to afford3-(2,3-dihydro-indol-1-yl)-3′,4′,5′,6′-tetrahydro-2′H-[2,4′]bipyridinyl-1′-carboxylicacid tert-butyl ester (95) (100 mg, 0.29 mmol, yield 32%).

ESI-MS (M+1): 380 calc. for C₂₃H₂₉N₃O₂ 379.

STEP 2.3-(2,3-DIHYDRO-INDOL-1-YL)-1′,2′,3′,4′,5′,6′-HEXAHYDRO-[2,4′]BIPYRIDINYLHYDROCHLORIDE (96)

To3-(2,3-dihydro-indol-1-yl)-3′,4′,5′,6′-tetrahydro-2′H-[2,4′]bipyridinyl-1′-carboxylicacid tert-butyl ester (95) (100 mg, 0.29 mmol) was added 4 M HCl in MeOH(20 mL). The reaction mixture was stirred at RT for 1 h. Then it wasconcentrated to give3-(2,3-dihydro-indol-1-yl)-1′,2′,3′,4′,5′,6′-hexahydro-[2,4′]bipyridinylhydrochloride (96) (0.083 g, 0.29 mmol, 100% yield) which was used inthe next step without further purification.

ESI-MS (M+1): 280 calc. for C₁₈H₂₁N₃ 279.

Preparation 31

STEP 1. 3-(3-BROMO-QUINOLIN-2-YL)-AZETIDINE-1-CARBOXYLIC ACID TERT-BUTYLESTER (98)

A 100 mL 3-neck round bottom flask fitted with a magnetic stirrer andflushed with nitrogen was charged with zinc dust (813 mg, preactivatedaccording to the above Preparation 1, 12.7 mmol, 2.0 eq.) and DMA (10mL, anhydrous). 1,2-dibromoethane (236 mg, 1.27 mmol, 0.2 eq) was addedslowly, followed by TMSCl (137 mg, 1.27 mmol, 0.2 eq). The reaction wasstirred for 15 min at RT. A solution of N-Boc-3-iodoazetidine (2) (2.7g, 9.5 mmol, 1.5 eq) in DMA (10 mL, anhydrous) was added dropwise. Thesuspension was stirred for 1 h at RT.

A 100 mL 3-neck round bottom flask fitted with a mechanical stirrer wascharged with 2,3-dibromo-quinoline (97) (1.82 g, 6.4 mmol, 1.0 eq),PdCl₂(dppf) (446 mg, 0.64 mmol, 0.1 eq), CuI (121 mg, 0.64 mmol, 0.1eq), and DMA (20 mL, anhydrous). The dark solution was degassed for 15min. The clear zinc reagent solution above the residual solid zinc wastransferred to the above 100 mL flask by cannulation. The dark solutionwas degassed and heated to 80° C. for 16 h. The reaction was dilutedwith brine and extracted with EtOAc (3×100 mL). The combined organicswere washed with water (2×100 mL) and brine (100 mL), followed by dryingover sodium sulfate. The solution was concentrated and the residue waspurified by flash column chromatography (EtOAc:Petro ether=4:1) providesthe title compound (98) (1.2 g, 3.30 mmol, 52% yield) as a light yellowsolid.

ESI-MS (M+1): 363 calc. for C₁₇H₁₉BrN₂O₂ 362.

STEP 2. 3-(3-PHENYL-QUINOLIN-2-YL)-AZETIDINE-1-CARBOXYLIC ACIDTERT-BUTYL ESTER (99)

To a stirred solution of3-(3-bromo-quinolin-2-yl)-azetidine-1-carboxylic acid tert-butyl ester(98) (174 mg, 0.48 mmol) in dioxane (10 mL) was added phenylboronic acid(78) (87 mg, 0.71 mmol), Na₂CO₃ (152 mg, 1.4 mmol) and H₂O (2 mL). Thereaction mixture was degassed with N₂ and then PdCl₂(dppf) (35 mg, 0.05mmol) was added. The reaction mixture was stirred at 80° C. for 12 h.The reaction mixture was left to reach RT and filtered through a pad ofCELITE® and the filter cake was washed with CH₂Cl₂ (20 mL×3). Thecombined filtrates were evaporated in vacuo and the residue was purifiedby column chromatography ((EtOAc:Petrol ether=3:1) to give the desiredcompound (95) (154 mg, 0.42 mmol, 87% yield).

ESI-MS (M+1): 361 calc. for C₂₃H₂₄N₂O₂ 360.

STEP 3. 2-AZETIDIN-3-YL-3-PHENYL-QUINOLINE HYDROCHLORIDE (100)

A mixture of 3-(3-phenyl-pyridin-2-yl)-azetidine-1-carboxylic acidtert-butyl ester (99) (216 mg, 0.60 mmol) in 4 M HCl/MeOH solution (10mL) was stirred at RT. for 30 min. Then the solvent was evaporated at40° C. to give 2-azetidin-3-yl-3-phenyl-pyridine (100) (177 mg, 100%yield) as a yellow solid.

ESI-MS (M+1): 261 calc. for C₁₈H₁₆N₂ 260.

Preparation 32

STEP 1.3-BROMO-3′,4′,5′,6′-TETRAHYDRO-2′H-[2,4′]BIPYRIDINYL-1′-CARBOXYLIC ACIDTERT-BUTYL ESTER (101)

A 100 mL 3-neck round bottom flask fitted with a magnetic stirrer andflushed with nitrogen was charged with zinc dust (813 mg, preactivatedaccording to the above Preparation 1, 12.7 mmol, 2.0 eq.) and DMA (10mL, anhydrous). 1,2-dibromoethane (236 mg, 1.27 mmol, 0.2 eq) was addedslowly, followed by TMSCl (137 mg, 1.27 mmol, 0.2 eq). The reaction wasstirred for 15 min at RT. A solution of 4-Iodo-piperidine-1-carboxylicacid tert-butyl ester (38) (2.95 g, 9.5 mmol, 1.5 eq) in DMA (10 mL,anhydrous) was added dropwise. The suspension was stirred for 1 h at RT.

A 100 mL 3-neck round bottom flask fitted with a mechanical stirrer wascharged with 2,3-dibromo-pyridine (1) (1.5 g, 6.4 mmol, 1.0 eq),PdCl₂(dppf) (446 mg, 0.64 mmol, 0.1 eq), CuI (121 mg, 0.64 mmol, 0.1eq), and DMA (20 mL, anhydrous). The dark solution was degassed for 15min. The clear zinc reagent solution above the residual solid zinc wastransferred to the above 100 mL flask by cannulation. The dark solutionwas degassed and heated to 80° C. for 16 h. The reaction was dilutedwith brine and extracted with EtOAc (3×100 mL). The combined organicswere washed with water (2×100 mL) and brine (100 mL), followed by dryingover sodium sulfate. The solution was concentrated and the residue waspurified by flash column chromatography (PE:EtOAc=2:1) provides thetitle compound (101) (761 mg, 2.3 mmol, 35% yield) as a light yellowsolid.

ESI-MS (M+1): 341 calc. for C₁₅H₂₁BrN₂O₂ 340.

STEP 2.3-PHENYL-3′,4′,5′,6′-TETRAHYDRO-2′H-[2,4′]BIPYRIDINYL1′-CARBOXYLIC ACIDTERT-BUTYL ESTER (102)

To a stirred solution of3-bromo-3′,4′,5′,6′-tetrahydro-2′H-[2,4′]bipyridinyl-1′-carboxylic acidtert-butyl ester (101) (163 mg, 0.48 mmol) in dioxane (10 mL) was addedphenylboronic acid (78) (87 mg, 0.71 mmol), Na₂CO₃ (152 mg, 1.4 mmol)and H₂O (2 mL). The reaction mixture was degassed with N₂ and thenPdCl₂(dppf) (35 mg, 0.05 mmol) was added. The reaction mixture wasstirred at 80° C. for 12 h. The reaction mixture was left to reach RTand filtered through a pad of CELITE® and the filter cake was washedwith CH₂Cl₂ (20 mL×3). The combined filtrates were evaporated in vacuoand the residue was purified by column chromatography ((EtOAc:Petrolether=4:1) to give the desired compound (102) (138 mg, 0.41 mmol, 85%yield).

ESI-MS (M+1): 339 calc. for C₂₁H₂₆N₂O₂ 338.

STEP 3. 3-PHENYL-1′,2′,3′,4′,5′,6′-HEXAHYDRO-[2,4′]BIPYRIDINYLHYDROCHLORIDE (103)

A mixture of3-phenyl-3′,4′,5′,6′-tetrahydro-2′H-[2,4′]bipyridinyl-1′-carboxylic acidtert-butyl ester (102) (202 mg, 0.60 mmol) in HCl/MeOH solution (5 mL)was stirred at RT. for 30 min. Then the solvent was evaporated at 40° C.to give 3-phenyl-1′,2′,3′,4′,5′,6′-hexahydro-[2,4′]bipyridinylhydrochloride (103) (162 mg, 0.60 mmol, 100% yield) as a yellow solid.

ESI-MS (M+1): 239 calc. for C₁₆H₁₈N₂ 238.

Preparation 33

STEP 1. 3-PHENYL-N—O-TOLYL-ACRYLAMIDE (106)

A solution of o-tolylamine (104) (5.3 g, 50.0 mmol) in DCM (50 mL) wasadded to a stirring mixture of pyridine (5 mL) and DMAP (0.61 g, 5.0mmol) in DCM (20 mL) at 0° C. under N₂. The mixture was stirred for 15min before a solution of cinnamoyl chloride (105) (8.3 g, 50.0 mmol) inDCM (50 mL) was added over 10 min. After being stirred for further 15min, the mixture was allowed to warm to RT. The precipitate formed wascollected, washed with cold DCM and dried to afford the title compound(106) (9.9 g, 42.0 mmol, 84% yield).

STEP 2. 8-METHYL-1H-QUINOLIN-2-ONE (107)

An intimate mixture of the 3-phenyl-n-o-tolyl-acrylamide (106) (5 g, 2.1mmol) and aluminum chloride (0.83 g, 6.3 mmol) was heated rapidly tomelting then heated at 100° C. for 1 h. After cooling to RT, iced waterwas added and the resultant precipitate was washed with water and 5%aqueous hydrochloric acid to give (107) (2.9 g, 1.8 mmol, 87% yield).ESI-MS (M+1): 160 calc. for C₁₀H₉NO 159.

STEP 3. 2-CHLORO-8-METHYL-QUINOLINE (108)

A mixture of 8-methyl-1H-quinolin-2-one (107) (580 mg, 3.6 mmol) andphosphorus oxychloride (5 mL) was stirred at 60° C. overnight. Themixture was then poured onto ice water and extracted with DCM (3×50 mL).The combined extracts were washed with water (2×100 mL) and dried withNa₂SO₄, and the solvent was removed. The residue was chromatographed onsilica gel using 5% to 20% EtOAc in petroleum ether to give product(108) as small colorless crystals (400 mg, 2.3 mmol, 63% yield).

The following Table 10 lists compounds of Preparation P33.1 to P33.12,which were made analogous to Preparation 33 by using the appropriatematerials.

TABLE 10 PREPARATION P33.1 TO P33.12 Chemical ESI-MS Ex. # StructureName (M + 1) P33.1

N-(o-tolyl) cinnamamide 238 P33.2

N-(4- fluorophenyl) cinnamamide 242 P33.3

N-(3- fluorophenyl) cinnamamide 242 P33.4

N-(2- chlorophenyl) cinnamamide 258 P33.5

8-Methyl-1H- quinolin-2-one 160 P33.6

6-Fluoro-1H- quinolin-2-one 164 P33.7

7-Fluoro-1H- quinolin-2-one 164 P33.8

8-Chloro-1H- quinolin-2-one 180 P33.9

2-chloro-8- methyl- quinoline 178 P33.10

2-chloro-6- fluoro- quinoline 182 P33.11

2-chloro-7- fluoro- quinoline 182 P33.12

2,8- dichloro- quinoline 198

Preparation 34

STEP 1. 6-CHLOROQUINAZOLIN-2-AMINE (110)

A mixture of 5-chloro-2-fluoro-benzaldehyde (109) (5 g, 31.6 mmol) andguanidine carbonate (7.5 g, 41.1 mmol) was heated at 140° C. in DMA (50mL) for 3 h. 100 ml water was added and after refrigeration, a solid wasisolated by filtration, and dried under vacuum to give the product (110)(2.8 g, 15.8 mmol, 50% yield). ESI-MS (M+1): 180 calc. for C₈H₆ClN₃ 179.

STEP 2. 2,6-DICHLORO-QUINAZOLINE (111)

To a suspension of 6-chloro-quinazolin-2-ylamine (110) (2.8 g, 15.8mmol) and SbCl₃ (7.2 g, 32 mmol) in 1,2-dichloroethane (100 mL) wasadded tert-butylnitrate (6.2 ml, 52 mmol) and heated at 60° C. for 3 hunder nitrogen atmosphere. To the mixture was added aqueous saturatedNaHCO₃ and the mixture was filtered off and filtrate was extracted withCHCl₃. The organic layer was washed with brine, dried over Na₂SO₄, andevaporated. The residue was purified by silica gel columnchromatography, using CHCl₃/EtOAc (9:1, v/v) as eluent to give2,6-dichloro-quinazoline (111) (0.65 g, 3.12 mmol, 20% yield).

The following Table 11 lists compounds of Preparation P34.1 to P34.8,which were made analogous to Preparation 34 by using the appropriatematerials.

TABLE 11 PREPARATION P34.1 TO P34.8 ESI-MS Ex. # Structure Chemical Name(M + 1) P34.1

6-chloroquinazolin- 2-amine 180 P34.2

8-chloroquinazolin- 2-amine 180 P34.3

7-chloroquinazolin- 2-amine 180 P34.4

5-chloroquinazolin- 2-amine 180 P34.5

2,6-dichloro- quinazoline 199 P34.6

2,8-dichloro- quinazoline 199 P34.7

2,7-dichloro- quinazoline 199 P34.8

2,5-dichloro- quinazoline 199

Preparation 35

2-CHLORO-1,6-NAPHTHYRIDINE (113)

A mixture of phosphoryl trichloride (5.17 ml, 56.5 mmol) and1,6-naphthyridin-2(1H)-one (112) (1.65 g, 11.29 mmol, Alfa Aesar) wasstirred at 70° C. for 16 h. The reaction mixture was cooled to RT andwas poured onto 150 g of ice carefully. EtOAc (50 mL) was added and themixture was treated carefully with about 30 mL of 5 M NaOH until thefinal pH is persistently >10. The mixture was vigorously mixed, thentransferred into a separatory funnel. The EtOAc layer was then separatedand dried and re-suspended in 30 mL of DCM, the insoluble solids werefiltered off. The filtrate was loaded onto a silica gel pad and flushedwith 30% EtOAc in hexanes to give a solid after drying. The solid wasinitially white but changed color to yellow after drying on the highvacuum line over night. Yield; 1.19 g, 64%. The material (113) was useddirectly in the next step without any further purification.

Preparation 36

(1H-BENZOIMIDAZOL-2-YL)-[3-(3-CHLORO-PYRAZIN-2-YL)-AZETIDIN-1-YL]-METHANONE(84)

A mixture of 1H-benzoimidazole-2-carboxylic acid (19) (100 mg, 0.47mmol), 2-azetidin-3-yl-3-chloro-pyrazine hydrochloride (8) (96 mg, 0.47mmol), HATU (540 mg, 1.3 mmol) and Et₃N (101 mg, 1 mmol) in dry DCM (10mL) was stirred at RT overnight . Then the mixture reaction was pouredinto saturated aqueous Na₂CO₃ and extracted with DCM (50 mL×3), theorganic layer was washed with brine, dried over Na₂SO₄ and concentratedto give the crude compound which was purified by ISCO silica gel column(10% to 80% EtOAc in petroleum ether) and followed by reverse phaseprep. HPLC (10% to 80% water/MeCN) to afford pure(1H-benzoimidazol-2-yl)-[3-(3-chloro-pyrazin-2-yl)-azetidin-1-yl]-methanone(84) (50 mg, 0.16 mmol, yield 34%).

¹H-NMR (400 MHz, d₆-DMSO) δ (ppm) 8.67 (d, J=2.8 Hz, 1H); 8.43 (d, J=6.4Hz, 1H); 7.63 (br, 2H); 7.25 (s, 2H); 5.10-5.08 (m, 1H); 4.97-4.93 (m,1H); 4.51-4.39 (m, 3H).

ESI-MS (M+1): 314 calc. for C₁₅H₁₂ClN₅O 313.

The following Table 12 lists compound of Preparation P36.1, which wasmade analogous to Preparation 36 by using the appropriate materials.

TABLE 12 Chemical ESI-MS Ex. # Structure Name (M + 1) P36.1

(7-chloro- 1H-benzo[d] imidazol-2- yl)(3-(3- chloropyrazin- 2-yl)azetidin- 1-yl) methanone 348

Preparation 37

STEP 1.3-[3-(3,6-DIHYDRO-2H-PYRAN-4-YL)-PYRAZIN-2-YL]-AZETIDINE-1-CARBOXYLICACID TERT-BUTYL ESTER (115)

To a solution of 3-(3-chloro-pyrazin-2-yl)-azetidine-1-carboxylic acidtert-butyl ester (7) (1.0 g, 3.7 mmol) in dioxane (16 mL) was added asolution of Na₂CO₃ (780 mg, 6.4 mmol) in 5 mL water, followed byadditional of4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyran(114) (purchased from WUXI APPTEC) (840 mg 4.0 mmol) and Pd(dppf)Cl₂ (80mg). The resulting mixture was heated to reflux overnight under N₂atmosphere. TLC showed that the staring material was consumedcompletely. The solution was filtered and the filtrate was concentratedto give the residue which was purified by ISCO silica gel column (10% to80% EtOAc in petroleum ether) to give the product3-[3-(3,6-dihydro-2H-pyran-4-yl)-pyrazin-2-yl]-azetidine-1-carboxylicacid tert-butyl ester (115) (938 mg, 2.96 mmol, yield 80%) as solid.ESI-MS (M+1): 318 calc. for C₁₇H₂₃N₃O₃ 317.

STEP 2:3-[3-(TETRAHYDRO-PYRAN-4-YL)-PYRAZIN-2-YL]-AZETIDINE-1-CARBOXYLIC ACIDTERT-BUTYL ESTER (116)

A mixture of (115) (938 mg, 2.96 mmol) and wet Pd—C (50%, 400 mg) inMeOH (30 mL) was stirred under H₂ (40 psi) at 30° C. overnight. Then thereaction mixture was filtered through CELITE® and washed with MeOH. Thefiltrate was concentrated to give the desired compound (116) (897 mg,2.81 mmol, yield 95%). ESI-MS (M+1): 320 calc. for C₁₇H₂₅N₃O₃ 319.

STEP 3. 2-AZETIDIN-3-YL-3-(TETRAHYDRO-PYRAN-4-YL)-PYRAZINE HYDROCHLORIDE(117)

To a solution of 4 N HCl in MeOH (10 mL) was added3-[3-(Tetrahydro-pyran-4-yl)-pyrazin-2-yl]-azetidine-1-carboxylic acidtert-butyl ester (116) (897 mg, 2.81 mmol) at 0° C. and the resultingmixture was stirred at RT for 1 h. The mixture was concentrated underreduced pressure to give2-azetidin-3-yl-3-(tetrahydro-pyran-4-yl)-pyrazine hydrochloride (117)(716 mg, yield 100%) which was used for the next step without furtherpurification. ESI-MS (M+1): 220 calc. for C₁₂H₁₇N₃O 219.

Preparation 38

STEP 1. OXETAN-3-YLIDENE-ACETIC ACID ETHYL ESTER (120)

To a solution of oxetan-3-one (118) (5 g, 69.4 mmol) in CH₂Cl₂ (50 mL)at 0° C. was added ethyl 2-triphenylphosphoranylideneacetate (119) (26.6g, 76.3 mmol). The solution was allowed to warm to RT and stirred for 15min. The reaction mixture was then filtered through a pad of silica(washing with 30 percent EtOAc:Petrol ether), and the solvent removedunder reduced pressure to give ethyl 2-(oxetan-3-ylidene)acetate (120)as a colourless viscous oil (8.15 g, 57.4 mmol, yield: 79%). ESI-MS(M+1): 142 calc. for C₇H₁₀O₃ 142.

STEP 2. 2-(3-ETHOXYCARBONYL-OXETAN-3-YL)-MALONIC ACID DIMETHYL ESTER(121)

To a solution of oxetan-3-ylidene-acetic acid ethyl ester (120) (5.0 g,35.2 mmol) in DMF (30 mL) at RT was added sodium hydride (60% wt inmineral oil) (4.2 g, 106 mmol). The mixture was stirred at RT for 60 minand malonic acid dimethyl ester (4.7 g, 35.2 mmol) was added. Thereaction mixture was stirred at RT for 4 h. Then the reaction mixturewas neutralized with saturated NH₄Cl (10 mL), diluted with EtOAc (30 mL)and water (30 mL). The aqueous phase was extracted with EtOAc (3×80 mL)and the combined organic extracts were washed with brine (100 mL), driedover MgSO₄, filtered, and concentrated to give the product (121) (8.0 g,30.8 mmol, yield: 87%). ESI-MS (M+1): 261 calc. for C₁₁H₁₆O₇ 260.

STEP 3. (3-ETHOXYCARBONYLMETHYL-OXETAN-3-YL)-ACETIC ACID ETHYL ESTER(122)

To a solution of 2-(3-Ethoxycarbonyl-oxetan-3-yl)-malonic acid dimethylester

(121) (5.0 g, 21.7 mmol) in DMSO (25 mL) was added NaCl (3.8 g, 65.1mmol). The solution was heated at 160° C. for 3 h. The reaction mixturewas diluted with EtOAc (30 mL) and water (30 mL). The aqueous phase wasextracted with EtOAc (3×100 mL) and the combined organic extracts werewashed with brine (100 mL), dried over MgSO₄, filtered, and concentratedto give the product (122) (2.3 g, 10 mmol, yield: 46° A). ESI-MS (M+1):231 calc. for C₁₁H₁₈O₅ 230.

STEP 4. 2-[3-(2-HYDROXY-ETHYL)-OXETAN-3-YL]-ETHANOL (123)

(3-Ethoxycarbonylmethyl-oxetan-3-yl)-acetic acid ethyl ester (122) (2.3g, 10 mmol) was dissolved in 20 ml of THF. This solution was cooled downto 0° C. using an ice bath and AlLiH₄ (1.1 g, 30 mmol) was added byportions. The reaction mixture was stirred for 4 h at ambienttemperature, and then saturated aqueous solution of ammonium chloride(20 mL) was added. THF was evaporated off under reduced pressure, thenthe reaction mixture was taken up in ethyl acetate. The organic phasewas separated from the aqueous phase. This extraction was repeated onemore time and then the organic phases were combined and washed withbrine (100 mL), dried over MgSO₄, filtered, and concentrated to give theproduct (123) (1.3 g, 8.9 mmol, yield: 89%). ESI-MS (M+1): 147 calc. forC₇H₁₄O₃ 146.

STEP 5. METHANESULFONIC ACID2-[3-(2-METHANESULFONYLOXY-ETHYL)-OXETAN-3-YL]-ETHYL ESTER (124)

To a solution of 2-[3-(2-Hydroxy-ethyl)-oxetan-3-yl]-ethanol (123) (1.3g, 8.9 mmol) in CH₂Cl₂ (20 mL) at 0° C. was added Et₃N (2.7 g, 26.7mmol) and methanesulfonyl chloride (2.0 g, 17.8 mmol). The solution wasallowed to warm to RT and stirred for 15 min. The reaction mixture wasdiluted with water (80 mL). The aqueous phase was extracted with CH₂Cl₂(3×50 mL) and the combined organic extracts were washed with brine (100mL), dried over MgSO₄, filtered, and concentrated to give the product(124) (2.0 g, 6.6 mmol, yield: 74%). ESI-MS (M+1): 303 calc. forC₉H₁₈O₇S₂ 302.

STEP 6. 7-(2,4-DIMETHOXY-BENZYL)-2-OXA-7-AZA-SPIRO[3.5]NONANE (125)

To a solution of (124) (2.0 g, 6.6 mmol) in MeCN (20 mL) were added2,4-dimethoxy-benzylamine (1.2 g, 7.3 mmol) and Et₃N (2.0 g, 19.8 mmol).The solution was allowed to heat at reflux for 12 h. The reactionmixture was then filtered through a pad of silica (washing with 30percent EtOAc:Petrol ether), and the solvent removed under reducedpressure to give the product (125) (1.2 g, 4.3 mmol, yield: 65%). ESI-MS(M+1): 278 calc. for C₁₆H₂₃NO₃ 277.

STEP 7. 2-OXA-7-AZA-SPIRO[3.5]NONANE (126)

To a solution of 7-(2,4-Dimethoxy-benzyl)-2-oxa-7-aza-spiro[3.5]nonane(125) (300 mg, 1.1 mmol) in MeOH (10 mL) was added Pd(OH)₂ (300 mg). Thereaction solution was stirred at RT overnight under H₂ atmosphere. LCMSshowed that most of the staring material was consumed. The mixture wasfiltered and concentrated to give the product (126) (112 mg, 0.88 mmol,yield: 80%). ESI-MS (M+1): 128 calc. for C₇H₁₃NO 127.

Preparation 39

STEP 1. 6-ETHYL-2-OXA-6-AZA-SPIRO[3.3]HEPTANES (128)

To a solution of 3-bromo-2,2-bis(bromomethyl)propanol (127) (3.25 g, 10mmol) and potassium hydroxide (1.12 g, 20 mmol, in 10 mL water) in EtOH(20 mL) were added toluene-4-sulfonamide (3.76 g, 22 mmol). The reactionmixture was refluxed for 2 h, evaporated to remove EtOH then dilutedwith EAOAc (20 mL), washed with H₂O (20 mL). The organic layer waswashed with brine (20 mL), dried over Na₂SO₄, and filtered, evaporatedto give the product to give6-(toluene-4-sulfonyl)-2-oxa-6-aza-spiro[3.3]heptane (128) (1.6 g, 6.3mmol, yield: 63%).

ESI-MS (M+1): 128 calc. for C₇H₁₃NO 127.

STEP 2. 2-OXA-6-AZA-SPIRO[3.3]HEPTANE OXALATE SALT (129)

A mixture of 6-(toluene-4-sulfonyl)-2-oxa-6-aza-spiro[3.3]heptane (128)(1.27 g, 5 mmol) in MeOH (10 mL) was added magnesium chips. The mixturewas reacted using ultrasound at RT for 20 mins. Oxalic acid was addedand the mixture was stirred for 15 min, then concentrated to giveoxalate salt (129) (1.06 g, 3.68 mmol, yield: 73.6%).

¹H NMR: (D₂O, 400 MHz): δ (ppm) 4.76 (s, 4H), 4.23 (s, 4H). ESI-MS(M+1): 101 calc. for C₅H₉NO 100.

Preparation 40

STEP 1. 6-ACETYL-2,6-DIAZA-SPIRO[3.3]HEPTANE-2-CARBOXYLIC ACIDTERT-BUTYL ESTER (131)

To a solution of 2,6-diaza-spiro[3.3]heptane-2-carboxylic acidtert-butyl ester (130) (purchased from WUXI APPTEC®) ((500 mg, 2.73mmol) in CH₂Cl₂ (10 mL) were added KOH (459 mg, 8.19 mmol) and Ac₂O (279mg, 2.73 mmol). The reaction mixture was stirred at RT for 1 h, thendiluted with CH₂Cl₂ (20 mL), washed with H₂O (20 mL). The organic layerwas washed with brine (20 mL), dried over Na₂SO₄, and filtered,evaporated to give the product (131) (510 mg, 2.13 mmol, yield: 78%).ESI-MS (M+1): 241 calc. for C₁₂H₂₀N₂O₃ 240.

STEP 2. 1-(2,6-DIAZA-SPIRO[3.3]HEPT-2-YL)-ETHANONE HYDROCHLORIDE (132)

To a solution of 6-Acetyl-2,6-diaza-spiro[3.3]heptane-2-carboxylic acidtert-butyl ester (131) (300 mg, 1.33 mmol) in CH₂Cl₂ (10 mL) were addedTFA (388 mg, 4.0 mmol). The reaction mixture was stirred at RT for 1 h,then diluted with CH₂Cl₂ (20 mL), washed with H₂O (20 mL). The organiclayer was washed with brine (20 mL), dried over Na₂SO₄, and filtered,evaporated to give the product (132) (176 mg, 1.0 mmol, yield: 75%).ESI-MS (M+1): 141 calc. for C₇H₁₂N₂O 140.

Preparation 41

STEP 1. 2,2-DIMETHYL-3,6-DIHYDRO-2H-PYRAN-4-YL TRIFLUOROMETHANESULFONATEAND 6,6-DIMETHYL-3,6-DIHYDRO-2H-PYRAN-4-YL TRIFLUOROMETHANESULFONATE(134)

A solution of 2,2-dimethyltetrahydropyran-4-one (133) (115 g, 0.9 mol,1.0 eq.) in anhydrous THF (600 mL) was cooled to −78° C. and to it wasadded LDA (2.0 M, 538 mL, 1.08 mol, 1.2 eq.) drop wise under N₂ keepingthe internal temperature below −65° C. The resulting solution wasstirred at −78° C. for 20 min. A solution ofN-phenyl-bis(trifluoromethanesulfonimide) (353 g, 0.99 mol, 1.1 eq.) inanhydrous THF (1900 mL) was added to the above solution slowly keepingthe internal temperature below −65° C. The reaction mixture was warmedto room temperature slowly and stirred overnight. The reaction wasquenched with saturated aqueous sodium bicarbonate solution, andextracted with MTBE (2 L×2). The combined organic layers was washed with10% aqueous NaOH solution (1 L×2), brine (500 mL×2), dried over Na₂SO₄,filtered and concentrated to give crude title triflate product mixtureas dark brown oil. The crude product was extracted with hexanes (2 L×5)and the combined hexanes extracts was purified by column chromatography(directly loaded onto silica gel, Hexanes→15% ethyl acetate in hexanes,R_(f)=0.6, visualized with KMnO₄ stain) to give 200 g of the triflateproduct mixture (134) (a mixture of2,2-dimethyl-3,6-dihydro-2H-pyran-4-yl trifluoromethanesulfonate and6,6-dimethyl-3,6-dihydro-2H-pyran-4-yl trifluoromethanesulfonateratio=80.6:19.4 by GCMS) as a light yellow liquid (˜90% purity by GC-MSand ¹H NMR). This was taken to the next step without furtherpurification.

STEP 2.2-(2,2-DIMETHYL-3,6-DIHYDRO-2H-PYRAN-4-YL)-4,4,5,5-TETRAMETHYL-1,3,2-DIOXABOROLANEAND2-(6,6-DIMETHYL-3,6-DIHYDRO-2H-PYRAN-4-YL)-4,4,5,5-TETRAMETHYL-1,3,2-DIOXABOROLANE(136)

A mixture of compound 2,2-dimethyl-3,6-dihydro-2H-pyran-4-yltrifluoromethanesulfonate and 6,6-dimethyl-3,6-dihydro-2H-pyran-4-yltrifluoromethanesulfonate (134) (200 g, 0.77 mol, 1.0 eq.),bis(pinacolato)diboron (135) (195 g, 0.77 mol, 1.0 eq.), and potassiumacetate (151 g, 1.54 mol, 2.0 eq.) in dioxane (2 L) was degassed for 15min, to it was added 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (19 g, 0.023 mol, 0.03 eq.) and thereaction mixture was degassed again for 15 min. The reaction mixture washeated to 80° C. overnight, cooled, filtered through a medium frittedfunnel, and washed with MTBE (300 mL×4). The organic extracts werecombined and concentrated under reduced pressure. The crude productmixture (136) was cooled using an ice bath, stirred with an overheadstirrer and to it was added aqueous 2M NaOH solution (2 L) keeping theinternal temperature below 15° C. The basic aqueous solution wasextracted with MTBE (250 mL×3), and the organic extracts were discarded.The aqueous phase was cooled using an ice bath and the pH was adjustedto 3 to 5 with concentrated HCl keeping the internal temperature below10° C. The heterogeneous solution (off-white solid precipitated out atpH 3-5) was extracted with EtOAc (3 L and 1.5 L). The combined organiclayer was washed with water (1 L), brine (1 L), dried over Na₂SO₄,filtered and concentrated. The crude product mixture (136) was purifiedby column chromatography (Hexanes→>15% ethyl acetate in hexanes,R_(f)=0.5, visualized on KMnO₄) to give 125 g of2-(2,2-dimethyl-3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolaneand2-(6,6-dimethyl-3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolanemixture (136) as a white solid (58% overall yield, >97% purity by GCMSand ¹H NMR, The ratio of regioisomers was found to be 80.4:19.6).

GCMS: >97%

¹H NMR (300 MHz, CDCl₃) δ 6.46-6.43 (m, 1H), 4.06 (q, 2H, J=3.0 Hz),1.96-1.94 (m, 2H), 1.20 (s, 12H), 1.09 (s, 6H)

GCMS: 239 (M+1); calcd for C₁₃H₂₃BO₃: 238.13

Example 1.1(1H-BENZOIMIDAZOL-2-YL)-[3-(3-PHENYL-PYRIDIN-2-YL)-AZETIDIN-1-YL]-METHANONE

To a mixture of 1H-benzoimidazole-2-carboxylic acid (124 mg, 0.76 mmol)in DMF (5 mL) was added TEA (152 mg, 1.5 mmol) and HATU (347 mg, 0.92mmol). The reaction mixture was stirred for 5 min and2-azetidin-3-yl-3-phenyl-pyridine hydrochloride (100 mg, 0.76 mmol) wasadded. The reaction mixture was stirred at RT overnight. The mixture wasdiluted with water (10 mL), and extracted with EtOAc (2×20 mL). Thecombined organic extracts were washed with water (5 mL) and brine (5mL), dried over Na₂SO₄, and filtered. The filtrate was evaporated invacuo and the residue was purified by column chromatography to give(1H-benzoimidazol-2-yl)-[3-(3-phenyl-pyridin-2-yl)-azetidin-1-yl]-methanone(100 mg, 0.28 mmol, 59% yield) as a light yellow solid.

The following Table 13A lists compounds of Examples 1.1 to 1.17, whichwere made analogous to Scheme 1 by using the appropriate materials andreaction conditions, which are listed in Table 13B. The NMR of theExamples are listed in Table 13C.

TABLE 13A EXAMPLES 1.1 TO 1.17 ESI-MS IC₅₀ Ex. # Structure Chemical Name(M + 1) (uM) 1.1

(1H-Benzoimidazol-2-yl)-[3- (3-phenyl-pyridin-2-yl)-azetidin-1-yl]-methanone 355 0.0219 1.2

(1H-Benzoimidazol-2-yl)-[3- (5-fluoro-3-phenyl-pyridin-2-yl)-azetidin-1-yl]- methanone 373 0.843  1.3

(1H-benzoimidazol-2-yl)-[4- (3-phenyl-pyrazin-2-yl)-piperidin-1-yl]-methanone 384 0.092  1.4

Benzothiazol-2-yl-[3-(3- phenyl-pyrazin-2-yl)- azetidin-1-yl]-methanone373 0.446  1.5

(1H-Benzoimidazol-2-yl)-[3- (3-piperidin-1-yl-quinoxalin-2-yl)-azetidin-1-yl]- methanone 413 0.0271 1.6

(1H-Benzoimidazol-2-yl)- {3-[3-(4-hydroxy-piperidin-1-yl)-quinoxalin-2-yl]- azetidin-1-yl}-methanone 429 0.0115 1.7

(1H-Benzoimidazol-2-yl)-[3- (2,3-dihydro-indol-1-yl)-3′,4′,5′,6′-tetrahydro-2′H- [2,4′]bipyridinyl-1′-yl]- methanone 424 0.921.8

(1H-Benzoimidazol-2-yl)-[3- (3-phenyl-quinolin-2-yl)-azetidin-1-yl]-methanone 405 0.0834 1.9

(1H-Benzoimidazol-2-yl)-(3- phenyl-3′,4′,5′,6′-tetrahydro-2′H-[2,4′]bipyridinyl-1′-yl)- methanone 383 0.0217 1.10

(1H-Benzoimidazol-2-yl)- {4-[3-(4-hydroxymethyl-piperidin-1-yl)-pyrazin-2- yl]-piperidin-1-yl}- methanone 421 0.00981.11

(3-(3-phenylpyrazin-2- yl)azetidin-1-yl)(pyridin-2- yl)methanone 3170.828  1.12

(6-methylpyridin-2-yl)-(3-(3- phenylpyrazin-2-yl)azetidin-1-yl)methanone 331 3.67  1.13

(3-methylpyridin-2-yl)(3-(3- phenylpyrazin-2-yl)azetidin- 1-yl)methanone331 11.9   1.14

(5-methylpyridin-2-yl)(3-(3- phenylpyrazin-2-yl)azetidin- 1-yl)methanone331 2.03  1.15

(4-methylpyridin-2-yl)(3-(3- phenylpyrazin-2-yl)azetidin- 1-yl)methanone331 4.71  1.16

(1H-Benzoimidazol-2-yl)-[3- (3-phenyl-quinoxalin-2-yl)-azetidin-1-yl]-methanone 406 0.0335 1.17

(1H-Benzoimidazol-2-yl)-[3- (3-morpholin-4-yl-pyrazin-2-yl)-azetidin-1-yl]-methanone 365 0.14 

TABLE 13B STARTING MATERIALS AND REACTION CONDITION FOR PREPARATION OFEXAMPLES 1.1 TO 1.17 Ex. # Starting Material 1 Starting Material 2Reaction Condition 1.1

HATU, TEA, DMF 1.2

HATU, TEA, DMF 1.3

HATU, TEA, DMF 1.4

HATU, TEA, DMF 1.5

HATU, TEA, DMF 1.6

HATU, TEA, DMF 1.7

HATU, TEA, DMF 1.8

HATU, TEA, DMF 1.9

HATU, TEA, DMF 1.10

HATU, TEA, DMF 1.11

HATU, TEA, DMF 1.12

HATU, TEA, THF 1.13

HATU, TEA, THF 1.14

HATU, TEA, THF 1.15

HATU, TEA, THF 1.16

HATU, TEA, DMF 1.17

HATU, TEA, DCM

TABLE 13C 1H NMR δ (PPM) DATA FOR EXAMPLES 1.1 TO 1.17 Ex. # StructureNMR 1.1

(DMSO, 400 MHz): 8.61 (s, 1 H); 7.72-7.70 (m, 2 H); 7.66-7.20 (m, 10 H);4.88-4.86 (m, 2 H); 4.20- 4.13 (m, 3 H). 1.2

(CDCl₃, 400 MHz): 8.49 (d, J = 2.4 Hz, 1H); 8.13- 8.10 (m, 1H);7.67-7.66 (m, 2H); 7.55-7.50 (m, 3H); 7.45-7.43 (m, 2H); 7.37-7.35 (m,2H); 4.99- 4.95 (m, 1H); 4.78-4.74 (m, 1H); 4.39-4.37 (m, 1 H);3.34-4.25 (m, 1H); 4.17-4.13 (m, 1H). 1.3

(CDCl₃, 400 MHz): 8.50 (s, 2H); 7.70-7.67 (m, 2H); 7.56-7.51 (m, 5H);7.37-7.26 (m, 2H); 6.06- 6.03 (m, 1H); 4.91-4.88 (m, 1H); 3.39-3.28 (m,2H); 2.90-2.84 (m, 1H); 2.17-2.11 (m, 2H); 2.01- 1.90 (m, 2H). 1.4

(CDCl₃, 400 MHz): 8.60 (dd, J = 2.4, 17.2 Hz, 2H); 8.06 (d, J = 7.6 Hz,1H); 7.96 (d, J = 7.2 Hz, 1H); 7.56-7.45 (m, 7H); 5.15-5.06 (m, 2H);4.53- 4.42 (m, 2H); 4.39-4.32 (m, 1H). 1.5

(DMSO, 400 MHz): 7.93-7.91 (m, 1H); 7.77-7.70 (m, 2H); 7.63-7.61 (m,1H); 7.55-7.49 (m, 2H); 7.28-7.22 (m, 2H); 5.13-5.11 (m, 1H); 5.01-5.00(m, 1H); 4.54-4.53 (m, 1H); 4.42-4.40 (m, 2H); 3.18-3.16 (m, 4H);1.71-1.68 (m, 4H); 1.61-1.59 (m, 2H). 1.6

(DMSO, 400 MHz): 7.92 (d, J = 7.6 Hz, 1H); 7.77- 7.71 (m, 2H); 7.65-7.63(m, 1H); 7.55-7.50 (m, 2H); 7.30-7.20 (m, 2H); 5.13-5.10 (m, 1H); 4.73(d, J = 4.0 Hz, 1H); 4.54-4.48 (m, 1H); 4.46-4.41 (m, 2H); 3.70-3.69 (m,3H); 3.49-3.44 (m, 2H); 2.99-2.95 (m, 2H); 1.95-1.91 (m, 2H); 1.63-1.58(m, 2H). 1.7

(CDCl₃, 400 MHz): 8.53 (d, J = 4.8 Hz, 1H); 8.30 (d, J = 8.4, 1H);7.78-7.68 (m, 3H); 7.52-7.45 (m, 2H); 7.37-7.31 (m, 1H); 7.10-7.03 (m,1H); 6.91- 6.87 (m, 1H); 6.34 (d, J = 7.6 Hz, 1H); 4.89-4.86 (m, 1H);4.30-4.27 (m, 1H); 3.82-3.73 (m, 3H); 3.50-3.38 (m, 1H); 3.34-3.25 (m,2H); 2.95-2.89 (m, 1H); 2.53-2.43 (m, 1H); 2.33-2.29 (m, 1H); 1.96-1.94(m, 1H); 1.89-1.85 (m, 1H). 1.8

(DMSO, 400 MHz): 8.22 (s, 1); 8.06 (d, J = 8.8 Hz, 1H); 7.99 (d, J = 8.0Hz, 1H); 7.74-7.69 (m, 2H); 7.60-7.45 (m, 8H); 7.27-7.21 (m, 2H); 5.08-5.06 (m, 1H); 4.88-4.86 (m, 1H); 4.35-4.33 (m, 2H); 4.14-4.13 (m, 1H).1.9

(CD₃OD, 400 MHz): 8.73-8.71 (m, 1H); 8.35-8.33 (m, 1H); 7.91-7.88 (m,1H); 7.68-7.88 (m, 1H); 7.58-7.54 (m, 3H); 7.45-7.43 (m, 2H); 7.40-7.37(m, 2H); 5.07-5.02 (m, 1H); 4.80-4.71 (m, 1H); 3.48-3.45 (m, 1H);3.28-3.25 (m, 1H); 2.90-2.80 (m, 1H); 2.15-2.00 (m, 4H). 1.10

(CD₃OD, 400 MHz): 8.14-8.12 (m, 1H); 8.10-8.08 (m, 1H); 7.76-7.74 (m,2H); 7.50-7.48 (m, 2H); 4.35 (d, J = 6.8 Hz, 1H); 3.50 (d, J = 6.4 Hz,2H); 3.46-3.43 (m, 4H); 3.31-3.30 (m, 2H); 3.15 (s, 1H); 2.92-2.89 (m,2H); 1.99-1.98 (m, 3H); 1.89 (d, J = 12.8 Hz, 3H); 1.71-1.48 (m, 2H).1.11

(CD₃OD, 400 MHz): 8.65 (d, J = 2.4 Hz, 1H), 8.53 (d, J = 2.4 Hz, 2H),7.98-7.89 (m, 2H), 7.52-7.47 (m, 6H), 4.90-4.86 (m, 2H), 4.39-4.26 (m,3H). 1.12

(CD₃OD, 400 MHz): 8.64 (d, J = 2.4 Hz, 1H), 8.53 (d, J = 2.8 Hz, 1H),7.91-7.87 (m, 1H), 7.80 (d, J = 8 Hz, 1H), 7.51-7.46 (m, 6H), 4.85-4.83(m, 2H), 4.37-4.31 (m, 3H), 2.54 (s, 3H). 1.13

(CD₃OD, 400 MHz): 8.53 (d, J = 2.4 Hz, 1H), 8.42 (d, J = 4.8 Hz, 1H),8.40 (s, 1H), 7.91-7.89 (m, 1H), 7.51-7.43 (m, 6H), 4.39-4.29 (m, 5H),2.45 (s, 3H). 1.14

(CD₃OD, 400 MHz): 8.63 (d, J = 2.4 Hz, 1H), 8.52 (d, J = 2.8 Hz, 1H),8.41 (s, 1H), 7.87 (d, J = 8.4 Hz, 1H), 7.76-7.73 (m, 1H), 7.50-7.46 (m,5H), 4.85-4.84 (m, 2H), 4.37-4.26 (m, 3H), 2.36 (s, 3H). 1.15

(CD₃OD, 400 MHz): 9.48 (d, J = 2.4 Hz, 1H), 9.42 (d, J = 2.8 Hz, 1H),9.22 (d, J = 5.2 Hz, 1H), 8.58- 8.57 (m, 1H), 8.31 (s, 5H), 8.14-8.12(m, 1H), 5.61-5.52 (m, 2H), 5.04-4.97 (m, 3H), 3.15 (s, 3H). 1.16

(d-DMSO, 400 MHz): 8.17-8.11 (m, 2H); 7.86-7.85 (m, 2H); 7.67-7.48 (m,7H); 7.27-7.26 (m, 2H); 5.11-5.07 (m, 1H); 4.98-4.94 (m, 1H); 45.1-4.49(m, 1H); 4.39-4.35 (m, 1H); 4.27-4.22 (m, 1H). 1.17

(CDCl₃, 400 MHz): 8.23-8.22 (m, 1H); 8.16-8.15 (m, 1H); 7.17-7.69 (m,2H); 7.36-7.34 (m, 2H); 5.33 (t, J = 10.0 Hz, 1H); 5.10-5.06 (m, 1H);4.65- 4.59 (m, 2H); 4.35-4.25 (m, 1H); 3.88-3.89 (m, 4H); 3.17-3.14 (m,4H)

Example 2.1(1-METHYL-1H-BENZOIMIDAZOL-2-YL)-[3-(3-PHENYL-PYRAZIN-2-YL)-AZETIDIN-1-YL]-METHANONE

To a stirred solution of[3-(3-chloro-pyrazin-2-yl)-azetidin-1-yl]-(1-methyl-1H-benzoimidazol-2-yl)-methanone(100 mg, 0.30 mmol) in dioxane (10 mL) was added phenylboronic acid (87mg, 0.71 mmol), Na₂CO₃ (152 mg, 1.4 mmol) and H₂O (2 mL). The reactionmixture was degassed with N₂ and then PdCl₂(dppf) (35 mg, 0.05 mmol) wasadded. The reaction mixture was stirred at 80° C. for 12 h. The reactionmixture was left to reach RT and filtered through a pad of CELITE® andthe filter cake was washed with CH₂Cl₂ (20 mL×3). The combined filtrateswere evaporated in vacuo and the residue was purified by columnchromatography to give the desired compound (60 mg, 0.17 mmol, yield70%)

The following Table 14A lists compounds of Examples 2.1 to 2.30, whichwere made analogous to Scheme 2 by using the appropriate materials andreaction conditions, which are listed in Table 14B. The NMR data of theExamples are listed in Table 14C.

TABLE 14A EXAMPLES 2.1 TO 2.30 ESI-MS IC₅₀ Ex. # Structure Chemical Name(M + 1) (uM) 2.1

(1-Methyl-1H-benzoimidazol-2- yl)-[3-(3-phenyl-pyrazin-2-yl)-azetidin-1-yl]-methanone 370 0.181  2.2

[3-(3-Phenyl-pyrazin-2-yl)- azetidin-1-yl]-[1-(2,2,2-trifluoro-ethyl)-1H-benzoimidazol-2-yl]- methanone 438 0.893  2.3

(1H-Benzoimidazol-2-yl)-[3-(3- phenyl-pyrazin-2-yl)-azetidin-1-yl]-methanone 356 0.0248 2.4

(1H-Benzoimidazol-2-yl)-{3-[3- (3,4-dimethoxy-phenyl)-pyrazin-2-yl]-azetidin-1-yl}-methanone 416 0.0188 2.5

(1H-Benzoimidazol-2-yl)-{3-[3- (3-isopropyl-phenyl)-pyrazin-2-yl]-azetidin-1-yl}-methanone 398 0.049  2.6

(1H-Benzoimidazol-2-yl)-{3-[3- (3-trifluoromethoxy-phenyl)-pyrazin-2-yl]-azetidin-1-yl}- methanone 440 0.0357 2.7

1H-Benzoimidazol-2-yl)-{3-[3- (3,5-dimethoxy-phenyl)-pyrazin-2-yl]-azetidin-1-yl}-methanone 416 0.056  2.8

(1H-Benzoimidazol-2-yl)-{3-[3- (3-ethoxy-phenyl)-pyrazin-2-yl]-azetidin-1-yl}-methanone 400 0.0299 2.9

(1H-Benzoimidazol-2-yl)-{3-[3- (3-isopropyl-phenyl)-pyrazin-2-yl]-azetidin-1-yl}-methanone 414 0.0352 2.10

(1H-Benzoimidazol-2-yl)-{3-[3- (3-fluoro-5-methoxy-phenyl)-pyrazin-2-yl]-azetidin-1-yl}- methanone 404 0.424 2.11

(1H-Benzoimidazol-2-yl)-{3-[3- (2-methoxy-pyridin-4-yl)-pyrazin-2-yl]-azetidin-1-yl}-methanone 387 0.093 2.12

(1H-Benzoimidazol-2-yl)-{3-[3- (5-methoxy-pyridin-3-yl)-pyrazin-2-yl]-azetidin-1-yl}-methanone 387 0.640 2.13

(1H-Benzoimidazol-2-yl)(3-(3- (4-fluoro-3-methylphenyl)pyrazin-2-yl)azetidin-1-yl)methanone 388 0.013  2.14

(1H-Benzoimidazol-2-yl)-{3-[3- (4-methoxy-3-methyl-phenyl)-pyrazin-2-yl]-azetidin-1-yl}- methanone 400 0.0201 2.15

(1H-Benzoimidazol-2-yl)-{3-[3- (3-fluoro-5-methyl-phenyl)-pyrazin-2-yl]-azetidin-1-yl}- methanone 388 0.0393 2.16

(1H-Benzoimidazol-2-yl)-{3-[3- (5-methyl-pyridin-3-yl)-pyrazin-2-yl]-azetidin-1-yl}-methanone 371 0.195  2.17

(1H-Benzoimidazol-2-yl)-{3-[3- (4-methyl-thiophen-2-yl)-pyrazin-2-yl]-azetidin-1-yl}-methanone 376 0.013  2.18

(1H-Benzoimidazol-2-yl)-{3-[3- (1-methyl-1H-pyrazol-4-yl)-pyrazin-2-yl]-azetidin-1-yl}- methanone 360 0.216 2.19

(1H-Benzoimidazol-2-yl)-{3-[3- (3-hydroxymethyl-phenyl)-pyrazin-2-yl]-azetidin-1-yl}- methanone 386 0.0336 2.20

(1H-Benzoimidazol-2-yl)-{3-[3- (4-hydroxymethyl-phenyl)-pyrazin-2-yl]-azetidin-1-yl}- methanone 386 0.0398 2.21

1-(4-{3-[1-(1H-Benzoimidazole-2- carbonyl)-azetidin-3-yl]-pyrazin-2-yl}-phenyl)-ethanone 398 0.0247 2.22

1-(3-{3-[1-(1H-Benzoimidazole-2- carbonyl)-azetidin-3-yl]-pyrazin-2-yl}-phenyl)-ethanone 398 0.0151 2.23

(1H-Benzoimidazol-2-yl)-{3-[3- (3-methoxymethyl-phenyl)-pyrazin-2-yl]-azetidin-1-yl}- methanone 400 0.0449 2.24

4-{3-[1-(1H-Benzoimidazole-2- carbonyl)-azetidin-3-yl]-pyrazin-2-yl}-N,N-dimethyl-benzamide 427 0.026 2.25

3-{3-[1-(1H-Benzoimidazole-2- carbonyl)-azetidin-3-yl]-pyrazin-2-yl}-N,N-dimethyl-benzamide 427 0.537 2.26

(1H-benzo[d]imidazol-2-yl)(3-(3- (pyridin-4-yl)pyrazin-2-yl)azetidin-1-yl)methanone 357 0.25 2.27

(7-chloro-1H-benzo[d]imidazol-2- yl)(3-(3-(pyridin-3-yl)pyrazin-2-yl)azetidin-1-yl)methanone 391 0.587 2.28

(1H-benzo[d]imidazol-2-yl)(3-(3- (2-methylpyridin-4-yl)pyrazin-2-yl)azetidin-1-yl)methanone 371 0.037 2.29

(1H-benzo[d]imidazol-2-yl)(3-(3- (m-tolyl)pyrazin-2-yl)azetidin-1-yl)methanone 370 0.0148 2.30

3-(3-(1-(1H-benzo[d]imidazole-2- carbonyl)azetidin-3-yl)pyrazin-2-yl)benzonitrile 381 0.226

TABLE 14B STARTING MATERIALS AND REACTION CONDITION FOR PREPARATION OFEXAMPLES 2.1 TO 2.30 Ex. # Structure NMR 2.1

(CD₃OD, 400 MHz): 8.65(d, J = 2.4 Hz, 1 H); 8.53(d, J = 2.4, 1 H);7.70-7.67(m, 1 H); 7.59-7.58(m, 1 H); 7.53-7.40(m, 5 H); 7.38-7.35(m, 1H); 7.34-7.31(m, 1 H); 4.81-4.80(m, 2 H); 4.41-4.32(m, 1 H); 4.07(s, 3H). 2.2

(CD₃OD, 400 MHz): 8.67-8.66(m, 1 H); 8.53-8.52(m, 1 H); 7.74-7.72(m, 1H); 7.63-7.61(m, 1 H); 7.53-7.48 (m, 5 H); 7.45-7.41(m, 1 H);7.37-7.33(m, 1 H); 5.60- 5.56(m, 2 H); 4.94-4.92(m, 2 H); 4.41-4.34(m, 3H). 2.3

(CDCl₃, 400 MHz): 8.62-8.60(m, 2 H); 7.69-7.68(m, 2H); 7.57-7.44(m, 5H);7.43-7.32(m, 2H); 5.22-5.12 (m, 2H); 4.64-4.62(m, 1H); 4.52-4.34(m, 1H).2.4

(CDCl₃, 400 MHz): 8.51-8.48(m, 2 H); 7.72(br, 1H); 7.47(br, 1H);7.24(brs, 2H); 7.05(s, 1 H); 6.93(s, 2 H); 5.15-5.16(m, 2H);4.58-4.54(m, 1 H); 4.46-4.44(m, 1H); 4.38-4.30(m, 1 H); 3.90(s, 6 H) 2.5

(CDCl₃, 400 MHz): 8.60-8.57(m, 2 H); 7.67(brs, 2H); 7.46-7.44(m, 1H);7.38-7.37(m, 2 H); 7.31-7.26(m, 3 H); 5.17-5.16(m, 2H); 4.63-4.62(m,1H); 4.51-4.50(m, 1 H); 4.36-4.33(m, 1 H); 3.05-2.99(m, 2H); 1.33(d, J =6.8 Hz, 6H). 2.6

(DMSO, 400 MHz): 8.75-8.74(m, 1 H); 8.67-8.66(m, 1H); 7.69-7.54(m, 6H);7.27-7.25(m, 2H); 4.95-4.92 (m, 2H); 4.31-4.25(m, 3H). 2.7

(CDCl₃, 400 MHz): 8.60(d, J = 2.4 Hz, 1H); 8.56(d, J = 2.4 Hz, 1H);7.67(br, 2H); 7.43-7.40(m, 1H); 7.32- 7.30(m, 2H); 7.02-6.98(m, 3H);5.17-5.16(m, 2H); 4.66-4.60(m, 2H); 4.54-4.49(m, 1H); 4.40-4.36(m, 1H);1.38(d, J = 6.0 Hz, 6H). 2.8

(CDCl₃, 400 MHz): 8.63-8.59(m, 2 H); 7.70(br, 2 H); 7.44-7.28(m, 3 H);7.06-7.01(m, 3 H); 5.20-5.18(m, 2 H); 4.63-4.53(m, 2 H); 4.41-4.40(m, 1H); 4.15-4.10 (m, 2 H); 1.49-1.45(m, 3 H). 2.9

(DMSO, 400 MHz): 8.70(d, J = 2.4 Hz, 1H); 8.64(d, J = 2.4 Hz, 1 H);7.71(brs, 1H); 7.50-7.41(m, 5 H); 7.26 (brs, 2H); 5.32-5.29(m, 1 H);4.98-4.93(m, 2H); 4.61- 4.59(m, 2 H); 4.34-4.28(m, 2H); 4.24-4.21(m,1H). 2.10

(CDCl₃, 400 MHz): 8.62(d, J = 2.4 Hz, 1H); 8.57(d, J = 2.4 Hz, 1H);7.69-7.67(m, 2H); 7.34-7.32(m, 2H); 7.26-7.15(m, 2H); 6.96-6.92(m, 1H);5.19-5.14(m, 2H); 4.62(t, J = 6.0 Hz, 1H); 4.51(t, J = 9.2 Hz, 1H);4.37-4.34(m, 1H); 3.97(s, 3H) 2.11

(CDCl₃, 400 MHz): 8.70-8.69(m, 1H); 8.63-8.62(m, 1 H); 8.43-8.42(m, 1H); 7.74-7.72(m, 2 H); 7.43-7.41 (m, 2H); 7.12-7.11(m, 1 H); 7.01(s, 1H); 5.15-5.11(m, 2 H); 4.56-4.52(m, 2 H); 4.32-4.31(m, 1 H); 4.06(s, 3H). 2.12

(CDCl₃, 400 MHz): 8.66-8.65(m, 1H); 8.57-8.56(m, 2H); 8.50(s, 1H);7.96(s, 1H); 7.66-7.64(m, 2H); 7.36- 7.34(m, 2H); 5.09-5.00(m, 2H);4.59-4.46(m, 2H); 4.29-4.27(m, 1H); 4.00(s, 3H) 2.13

(CDCl₃, 400 MHz): 8.54(d, J = 1.6 Hz, 1H); 8.49(d, J = 2.4 Hz, 1H);7.62(s, 2H); 7.33-7.26(m, 3H); 7.19(s, 1H); 7.09(t, J = 8.8 Hz, 1H);5.13-5.10(m, 2H); 4.29- 4.18(m, 1H); 2.62(s, 3H). 2.14

(CDCl₃, 400 MHz): 8.56(s, 2H); 7.69(brs, 2H); 7.34- 7.24(m, 4 H);6.96-6.94(m, 1H); 5.21-5.15(m, 2H); 4.60-4.40(m, 3H); 3.90(s, 3H);2.30(s, 3H). 2.15

(CDCl₃, 400 MHz): 8.62-8.57(m, 2H); 7.67-7.67(m, 2H); 7.30(brs, 2 H);7.05-7.03(m, 3 H); 5.17-5.15(m, 2H); 4.62-4.48(m, 2H); 4.35-4.33(m, 1H); 2.46(s, 3 H). 2.16

(CDCl₃, 400 MHz): 8.83(s, 1H); 8.67(s, 1H); 8.65(d, J = 2.0 Hz, 1H);8.56(d, J = 2.0 Hz, 1H); 8.31(s, 1H); 7.65-7.62(m, 2H); 7.33-7.31(m,2H); 5.11-5.07(m, 1H); 5.03-5.00(m, 1H); 4.29-4.25(m, 1H); 2.57(s, 3H).2.17

(CDCl₃, 400 MHz): 8.58-8.54(m, 2 H); 7.61(br, 2 H); 7.40-7.38(m, 2 H);7.27-7.25(m, 2 H); 5.15-5.13(m, 1 H); 4.96-4.92(m, 1 H); 4.58-4.53(m, 2H); 4.38-4.36 (m, 1H); 2.29(s, 3H). 2.18

(CDCl₃, 400 MHz): 8.50-8.49(m, 2 H); 7.87(brs, 2H); 7.72(br, 2 H);7.41-7.40(m, 2H); 5.30-5.29(m, 1H); 5.08-5.07(m, 1 H); 4.65-4.61(m, 2H);4.49-4.48(m, 1H); 4.03(s, 3H). 2.19

(DMSO, 400 MHz): 8.70(d, J = 2.4 Hz, 1H); 8.64(d, J = 2.4 Hz, 1H);7.71(brs, 1H); 7.50-7.41(m, 5 H); 7.26 (brs, 2H); 5.32-5.29(m, 1H);4.98-4.93(m, 2H); 4.61- 4.59(m, 2H); 4.34-4.28(m, 2H); 4.24-4.21(m, 1H).2.20

(DMSO, 400 MHz): 8.69(d, J = 2.4 Hz, 1H); 8.63(d, J = 2.4 Hz, 1H);7.53-7.47(m, 5 H); 7.71(br, 2H); 4.97- 4.88(m, 2H); 4.59(s, 2 H);4.33-4.21(m, 3H). 2.21

(CDCl₃, 400 MHz): 8.65-8.61(m, 2 H); 8.12-8.10(m, 2 H); 7.70-7.68(m, 2H); 7.59-7.57(m, 2 H); 7.36-7.34 (m, 2 H); 5.21-5.10(m, 2 H);4.64-4.61(m, 1 H); 4.51- 4.50(m, 1 H); 4.32-4.29(m, 1 H); 2.68(s, 3H).2.22

(CDCl₃, 400 MHz): 8.63-8.59(m, 2 H); 8.09-8.07(m, 2H); 7.64-7.62(m, 4H);7.34-7.31(m, 2H); 5.15-5.14 (m, 2H); 4.60-4.58(m, 1H); 4.51-4.49(m, 1H);4.32- 4.30(m, 1H); 2.66(s, 3H). 2.23

(CDCl₃, 400 MHz): 8.63-8.59(m, 2 H); 7.70-7.68(m, 2H); 7.54-7.47(m, 3H);7.38-7.34(m, 3H); 7.02-7.00 (m, 4H); 5.16-5.12(m, 2H); 4.61-4.60(m, 1H);4.58- 4.51(m, 2H); 4.48-4.46(m, 1H); 4.39-4.33(m, 1H); 3.44(s, 3H). 2.24

(CDCl₃, 400 MHz): 8.58-8.54(m, 2 H); 7.67-7.66(m, 2 H); 7.57-7.54(m, 2H); 7.49-7.47(m, 2H); 7.34-7.32 (m, 2 H); 5.10-5.00(m, 2H); 4.52-4.51(m,1H); 4.41- 4.40(m, 1H); 4.27-4.21(m, 1H); 3.15(s, 3 H); 3.02(s, 3 H).2.25

(CDCl₃, 400 MHz): 8.60-8.55(m, 2 H); 7.66(brs, 2H); 7.57-7.50(m, 4H);7.30-7.29(m, 2H); 5.10(brs, 2H); 4.56-4.55(m, 1H); 4.45-4.44(m, 2H);4.29-4.27(m, 1H); 3.15(s, 3H); 3.04(s, 3H). 2.26

(CDCl₃, 400 MHz): 8.90-8.80(m, 2H); 8.70(s, 1H); 8.60(s, 1H);7.85-7.72(m, 2H); 7.67-7.62(m, 2H); 7.46-7.45(m, 2H); 5.24-5.13(m, 2H);4.66-4.62(m, 1H); 4.54-4.49(m, 1H); 4.30(brs, 1H). 2.27

(CDCl₃, 400 MHz): 8.75-8.72(m, 2H); 8.59(s, 1H); 8.54(s, 1H);7.84-7.83(m, 1H); 7.45-7.36(m, 2H); 7.24-7.11(m, 2H); 5.19-5.08(m, 2H);4.58-4.45(m, 2H); 4.29-4.22(m, 1H). 2.28

(CDCl₃, 400 MHz): δ (ppm) 8.69-8.60(m, 3H); 7.80(d, J = 8.0 Hz, 1H);7.55(d, J = 8.0 Hz, 1H); 7.32-7.26(m, 3H); 7.22-7.20(m, 1H);5.20-5.16(m, 2H); 4.68-4.64 (m, 1H); 4.55-4.51(m, 1H); 4.32-4.28(m, 1H);2.69(s, 3H). 2.29

(CDCl₃, 400 MHz): 8.60-8.57(m, 2H); 7.81-7.79(m, 1H); 7.55-7.40(m, 1H);7.34-7.26(m, 6H); 5.18-5.17 (m, 2H); 4.66-4.62(m, 1H); 4.52-4.48(m, 1H);4.38- 4.34(m, 1H); 2.46(s, 3H). 2.30

(CDCl₃, 400 MHz): δ (ppm) 8.69-8.68(m, 1H); 8.61- 8.60(m, 1H); 7.89(s,1H); 7.87-7.65(m, 5H); 7.32-7.26 (m, 2H); 5.25-5.13(m, 2H); 4.68-4.64(m,1H); 4.55- 4.51(m, 1H); 4.29-4.26(m, 1H).

TABLE 14C STARTING MATERIALS AND REACTION CONDITION FOR PREPARATION OFEXAMPLES 2.1 TO 2.30. Unless otherwise stated, all starting materialsare commercially available from common vendors. Ex. # Starting Material1 Starting Material 2 Reaction Condition 2.1

PdCl₂(dppf), Na₂CO₃, dioxane/H₂O 80° C. 2.2

PdCl₂(dppf), Na₂CO₃, dioxane/H₂O 80° C. 2.3

PdCl₂(dppf), K₃PO₄, dioxane/H₂O 80° C. 2.4

PdCl₂(dppf), K₃PO₄, dioxane/H₂O 80° C. 2.5

PdCl₂(dppf), K₃PO₄, dioxane/H₂O 80° C. 2.6

PdCl₂(dppf), K₃PO₄, dioxane/H₂O 80° C. 2.7

PdCl₂(dppf), K₃PO₄, dioxane/H₂O 80° C. 2.8

PdCl₂(dppf), K₃PO₄, dioxane/H₂O 80° C. 2.9

PdCl₂(dppf), K₃PO₄, dioxane/H₂O 80° C. 2.10

PdCl₂(dppf), K₃PO₄, dioxane/H₂O 80° C. 2.11

PdCl₂(dppf), K₃PO₄, dioxane/H₂O 80° C. 2.12

PdCl₂(dppf), K₃PO₄, dioxane/H₂O 80° C. 2.13

PdCl₂(dppf), K₃PO₄, dioxane/H₂O 80° C. 2.14

PdCl₂(dppf), K₃PO₄, dioxane/H₂O 80° C. 2.15

PdCl₂(dppf), K₃PO₄, dioxane/H₂O 80° C. 2.16

PdCl₂(dppf), K₃PO₄, dioxane/H₂O 80° C. 2.17

PdCl₂(dppf), K₃PO₄, dioxane/H₂O 80° C. 2.18

PdCl₂(dppf), K₃PO₄, dioxane/H₂O 80° C. 2.19

PdCl₂(dppf), K₃PO₄, dioxane/H₂O 80° C. 2.20

PdCl₂(dppf), K₃PO₄, dioxane/H₂O 80° C. 2.21

PdCl₂(dppf), K₃PO₄, dioxane/H₂O 80° C. 2.22

PdCl₂(dppf), K₃PO₄, dioxane/H₂O 80° C. 2.23

PdCl₂(dppf), K₃PO₄, dioxane/H₂O 80° C. 2.24

PdCl₂(dppf), K₃PO₄, dioxane/H₂O 80° C. 2.25

PdCl₂(dppf), K₃PO₄, dioxane/H₂O 80° C. 2.26

PdCl₂(dppf), K₃PO₄, dioxane/H₂O reflux 2.27

PdCl₂(dppf), K₃PO₄, dioxane/H₂O reflux 2.28

PdCl₂(dppf), K₂CO₃, dioxane/H₂O reflux 2.29

PdCl₂(dppf), K₂CO₃, dioxane/H₂O reflux 2.30

PdCl₂(dppf), K₂CO₃, dioxane/H₂O reflux

Example 3.1(1-METHYL-1H-BENZOIMIDAZOL-2-YL)-[3-(3-PIPERIDIN-1-YL-PYRAZIN-2-YL)-AZETIDIN-1-YL]-METHANONE

To a mixture of[3-(3-chloro-pyrazin-2-yl)-azetidin-1-yl]-(1-methyl-1H-benzoimidazol-2-yl)-methanone(0.10 g, 0.30 mmol), piperidine (0.052 g, 0.60 mmol) and triethylamine(0.091 g, 0.90 mmol) was added DMSO (4 mL). The solution was heated to120° C. for 5 h. Then the mixture was diluted with water (10 mL) andextracted with EtOAc (2×20 mL). The combined organic extracts werewashed with water (10 mL), brine (10 mL), dried over Na₂SO₄ andfiltered. The filtrate was evaporated in vacuo and the residue waspurified by flash column chromatography on silica gel (20% to 50% EtOAcin petroleum ether) to give(1-methyl-1H-benzoimidazol-2-yl)-[3-(3-piperidin-1-yl-pyrazin-2-yl)-azetidin-1-yl]-methanone(0.072 g, 0.19 mmol, 63% yield) as white solid.

The following Table 15A lists compounds of Examples 3.1 to 3.54, whichwere made analogous to Scheme 3 by using the appropriate materials andreaction conditions, which are listed in Table 15B. The NMR data of theExamples are listed in Table 15C.

TABLE 15A EXAMPLES 3.1 TO 3.54 ESI-MS IC₅₀ Ex. # Structure Chemical Name(M + 1) (uM) 3.1

(1-Methyl-1H- benzoimidazol-2-yl)-[3-(3- piperidin-1-yl-pyrazin-2-yl)-azetidin-1-yl]-methanone 377 0.136 3.2

{3-[3-(4-Hydroxy-piperidin- 1-yl)-pyrazin-2-yl]-azetidin-1-yl}-(1-methyl-1H- benzoimidazol-2-yl)- methanone 393 0.351 3.3

[3-(3-Piperidin-1-yl-pyrazin- 2-yl)-azetidin-1-yl]-[1-(2,2,2-trifluoro-ethyl)-1H- benzoimidazol-2-yl]- methanone 445 0.575 3.4

{3-[3-(4-Hydroxy-piperidin- 1-yl)-pyrazin-2-yl]-azetidin-1-yl}-[1-(2,2,2-trifluoro- ethyl)-1H-benzoimidazol-2- yl]-methanone 4610.963 3.5

(1H-Benzoimidazol-2-yl)-[3- (3-pyrrolidin-1-yl-pyrazin-2-yl)-azetidin-1-yl]-methanone 349 0.0217 3.6

(1H-Benzoimidazol-2-yl)-{3- [3-(4-trifluoromethyl-piperidin-1-yl)-pyrazin-2-yl]- azetidin-1-yl}-methanone 431 0.0205 3.7

(R & S)-(1H-Benzoimidazol- 2-yl)-{3-[3-(2-methyl-piperidin-1-yl)-pyrazin-2-yl]- azetidin-1-yl}-methanone 377 0.0636 3.8

(1H-Benzoimidazol-2-yl)-{3- [3-(3-methyl-piperidin-1-yl)-pyrazin-2-yl]-azetidin-1-yl}- methanone 377 0.016 3.9

(1H-benzoimidazol-2-yl)-{3- [3-(4-methyl-piperidin-1-yl)-pyrazin-2-yl]-azetidin-1-yl}- methanone 377 0.0272 3.10

(1H-Benzoimidazol-2-yl)-{3- [3-(4,4-dimethyl-piperidin-1-yl)-pyrazin-2-yl]-azetidin-1- yl}-methanone 391 0.0481 3.11

(1H-Benzoimidazol-2-yl)-{3- [3-(4-hydroxymethyl-piperidin-1-yl)-pyrazin-2-yl]- azetidin-1-yl}-methanone 393 0.0072 3.12

(1H-Benzoimidazol-2-yl)-(3- {3-[4-(1-hydroxy-1-methyl-ethyl)-piperidin-1-yl]- pyrazin-2-yl}-azetidin-1-yl)- methanone 4210.0563 3.13

(1H-Benzoimidazol-2-yl)-(3- {3-[4-(1-hydroxy-1-methyl-ethyl)-piperidin-1-yl]- pyrazin-2-yl}-azetidin-1-yl)- methanone 3930.0381 3.14

1-{3-[1-(1H- Benzoimidazole-2-carbonyl)- azetidin-3-yl]-pyrazin-2-yl}-piperidine-4-carbonitrile 388 0.00529 3.15

(1H-Benzoimidazol-2-yl)-{3- [3-(4-methoxymethyl-piperidin-1-yl)-pyrazin-2-yl]- azetidin-1-yl}-methanone 407 0.0185 3.16

(R & S)-(1H-Benzoimidazol- 2-yl)-{3-[3-(3-methyl-pyrrolidin-1-yl)-pyrazin-2- yl]-azetidin-1-yl}-methanone 363 0.008923.17

(R & S)-(1H- Benzoimidazol-2-yl)-{3-[3- (2-methyl-pyrrolidin-1-yl)-pyrazin-2-yl]-azetidin-1-yl}- methanone 363 0.0149 3.18

(1H-Benzoimidazol-2-yl)-{3- [3-(3,4-dihydro-1H-isoquinolin-2-yl)-pyrazin-2- yl]-azetidin-1-yl}-methanone 411 0.006763.19

(1H-Benzoimidazol-2-yl)-{3- [3-(1,3-dihydro-isoindol-2-yl)-pyrazin-2-yl]-azetidin-1- yl}-methanone 397 0.043 3.20

(R & S)-(1H-Benzoimidazol- 2-yl)-{3-[3-(3-phenyl-pyrrolidin-1-yl)-pyrazin-2- yl]-azetidin-1-yl}-methanone 425 0.0468 3.21

(R & S)-(1H-Benzoimidazol- 2-yl)-{3-[3-(2-phenyl-pyrrolidin-1-yl)-pyrazin-2- yl]-azetidin-1-yl}-methanone 425 0.163 3.22

(1H-Benzoimidazol-2-yl)-[3- (3-cyclopentylamino-pyrazin-2-yl)-azetidin-1-yl]- methanone 363 0.0363 3.23

(1H-Benzoimidazol-2-yl)-[3- (3-cyclohexylamino-pyrazin-2-yl)-azetidin-1-yl]- methanone 377 0.0389 3.24

(1H-Benzoimidazol-2-yl)-[3- (3-benzylamino-pyrazin-2-yl)-azetidin-1-yl]-methanone 385 0.171 3.25

(1H-Benzoimidazol-2-yl)-{3- [3-(2-hydroxy-ethylamino)-pyrazin-2-yl]-azetidin-1-yl}- methanone 339 0.74 3.26

(1H-benzo[d]imidazol-2- yl)(3-(3-((2- methoxyethyl)amino)pyrazin-2-yl)azetidin-1-yl)methanone 353 0.0586 3.27

1-{3-[1-(1H- Benzoimidazole-2-carbonyl)- azetidin-3-yl]-pyrazin-2-yl}-piperidine-4-carboxylic acid amide 406 0.00312 3.28

(R & S)-(1H-Benzoimidazol- 2-yl)-{3-[3-(3- hydroxymethyl-piperidin-1-yl)-pyrazin-2-yl]-azetidin-1- yl}-methanone 393 0.0206 3.29

(1H-Benzoimidazol-2-yl)-{3- [3-(3-hydroxy-piperidin-1-yl)-pyrazin-2-yl]-azetidin-1- yl}-methanone 379 0.0352 3.30

[3-(3-Azepan-1-yl-pyrazin-2- yl)-azetidin-1-yl]-(1H-benzoimidazol-2-yl)- methanone 379 0.0342 3.31

[3-(3-Azetidin-1-yl-pyrazin- 2-yl)-azetidin-1-yl]-(1H-benzoimidazol-2-yl)- methanone 335 0.0882 3.32

(R)-(1H-Benzoimidazol-2- yl)-{3-[3-(2-hydroxymethyl-pyrrolidin-1-yl)-pyrazin-2- yl]-azetidin-1-yl}-methanone 379 0.104 3.33

(1H-Benzoimidazol-2-yl)-[3- (3-isopropylamino-pyrazin-2-yl)-azetidin-1-yl]-methanone 337 0.133 3.34

(S)-(1H-Benzoimidazol-2- yl)-{3-[3-(2-hydroxymethyl-pyrrolidin-1-yl)-pyrazin-2- yl]-azetidin-1-yl}-methanone 379 0.917 3.35

(1H-Benzoimidazol-2-yl)-(3- {3-[4-(2-hydroxy-ethyl)-piperidin-1-yl]-pyrazin-2-yl}- azetidin-1-yl)-methanone 407 0.0094 3.36

(1H-Benzoimidazol-2-yl)-[3- (3-[1,4]oxazepan-4-yl-pyrazin-2-yl)-azetidin-1-yl]- methanone 379 0.0627 3.37

(1H-Benzoimidazol-2-yl)-{3- [3-(4-methyl-[1,4]diazepan-1-yl)-pyrazin-2-yl]-azetidin- 1-yl}-methanone 392 4.28 3.38

1-(4-{3-[1-(1H- Benzoimidazole-2-carbonyl)-azetidin-3-yl]-pyrazin-2-yl}- [1,4]diazepan-1-yl)-ethanone 420 0.08593.39

(1H-Benzoimidazol-2-yl)-{3- [3-(4-hydroxy-azepan-1-yl)-pyrazin-2-yl]-azetidin-1-yl}- methanone 393 0.0368 3.40

(R & S)-(1H- Benzoimidazol-2-yl)-{3-[3- (3-hydroxymethyl-pyrrolidin-1-yl)-pyrazin-2-yl]-azetidin- 1-yl}-methanone 379 0.0665 3.41

(R)-(1H-Benzoimidazol-2- yl)-{3-[3-(3-hydroxy-piperidin-1-yl)-pyrazin-2-yl]- azetidin-1-yl}-methanone 379 0.0709 3.42

(S)-(1H-Benzoimidazol-2- yl)-{3-[3-(3-hydroxy-piperidin-1-yl)-pyrazin-2-yl]- azetidin-1-yl}-methanone 379 0.170 3.43

(R & S)-1-{3-[1-(1H- Benzoimidazole-2-carobnyl)-azetidin-3-yl]-pyrazin-2-yl}- piperidine-3-carbonitrile 388 0.0868 3.44

1-{3-[1-(1H- Benzoimidazole-2-carbonyl)- azetidin-3-yl]-pyrazin-2-yl}-piperidine-4-carboxylic acid methylamide 420 0.016 3.45

1-{3-[1-(1H- Benzoimidazole-2-carbonyl)- azetidin-3-yl]-pyrazin-2-yl}-piperidine-4-carboxylic acid dimethylamide 434 0.0166 3.46

1-(1-(3-(1-(1H- benzo[d]imidazole-2- carbonyl)azetidin-3-yl)pyrazin-2-yl)piperidin-4- yl)ethanone 405 0.0119 3.47

1-(4-(3-(1-(1H- benzo[d]imidazole-2- carbonyl)azetidin-3-yl)pyrazin-2-yl)piperazin-1- yl)ethanone 406 0.192 3.48

(R)-(1H-benzo[d]imidazol-2- yl)(3-(3-(3- hydroxypyrrolidin-1-yl)pyrazin-2-yl)azetidin-1- yl)methanone 365 0.0718 3.49

(S)-(1H-benzo[d]imidazol-2- yl)(3-(3-(3- hydroxypyrrolidin-1-yl)pyrazin-2-yl)azetidin-1- yl)methanone 365 0.0632 3.50

(1H-benzo[d]imidazol-2- yl)(3-(3-(piperidin-1-yl)pyrazin-2-yl)azetidin-1- yl)methanone 363 0.0107 3.51

(1H-benzo[d]imidazol-2- yl)(3-(3-(4-hydroxypiperidin-1-yl)pyrazin-2-yl)azetidin-1- yl)methanone 379 0.0233 3.52

(1H-Benzoimidazol-2-yl)-{3- [3-(2-oxa-7-aza-spiro[3.5]non-7-yl)-pyrazin- 2-yl]-azetidin-1-yl}- methanone 405 0.02763.53

(1H-Benzoimidazol-2-yl)-{3- [3-(2-oxa-6-aza-spiro[3.3]hept-6-yl)-pyrazin- 2-yl]-azetidin-1-yl}- methanone 377 0.13203.54

1-(6-{3-[1-(1H- Benzoimidaozle-2-carbonyl)-azetidin-3-yl]-pyrazin-2-yl}- 2,6-diaza-spiro[3.3]hept-2- yl)-ethanone418 0.4900

TABLE 15B STARTING MATERIALS AND REACTION CONDITION FOR PREPARATION OFEXAMPLES 3.1 TO 3.54. Unless otherwise stated, all starting materialsare commercially available from common vendors. Ex. # Starting Material1 Starting Material 2 Reaction Condition 3.1

TEA, DMSO 120° C. 3.2

TEA, DMSO 120° C. 3.3

TEA, DMSO 120° C. 3.4

TEA, DMSO 120° C. 3.5

TEA, DMSO 120° C. 3.6

TEA, DMSO 120° C. 3.7

TEA, DMSO 120° C. 3.8

TEA, DMSO 120° C. 3.9

TEA, DMSO 120° C. 3.10

TEA, DMSO 120° C. 3.11

TEA, DMSO 120° C. 3.12

TEA, DMSO 120° C. 3.13

TEA, DMSO 120° C. 3.14

TEA, DMSO 120° C. 3.15

TEA, DMSO 120° C. 3.16

TEA, DMSO 120° C. 3.17

TEA, DMSO 120° C. 3.18

TEA, DMSO 120° C. 3.19

TEA, DMSO 120° C. 3.20

TEA, DMSO 120° C. 3.21

TEA, DMSO 120° C. 3.22

TEA, DMSO 120° C. 3.23

TEA, DMSO 120° C. 3.24

TEA, DMSO 120° C. 3.25

TEA, DMSO 120° C. 3.26

TEA, DMSO 120° C. 3.27

TEA, DMSO 120° C. 3.28

TEA, DMSO 120° C. 3.29

TEA, DMSO 120° C. 3.30

TEA, DMSO 120° C. 3.31

TEA, DMSO 120° C. 3.32

TEA, DMSO 120° C. 3.33

TEA, DMSO 120° C. 3.34

TEA, DMSO 120° C. 3.35

TEA, DMSO 120° C. 3.36

TEA, DMSO 120° C. 3.37

TEA, DMSO 120° C. 3.38

TEA, DMSO 120° C. 3.39

TEA, DMSO 120° C. 3.40

TEA, DMSO 120° C. 3.41

TEA, DMSO 120° C. 3.42

TEA, DMSO 120° C. 3.43

TEA, DMSO 120° C. 3.44

TEA, DMSO 120° C. 3.45

TEA, DMSO 120° C. 3.46

TEA, DMSO 120° C. 3.47

36.1 μW, 145° C. 36.2 Et₃N, Ac₂O, DCM 3.48

K₂CO₃, iPrOH, H₂O, 160° C. μW 3.49

K₂CO₃, iPrOH, H₂O, 160° C. μW 3.50

K₂CO₃, i-PrOH, H₂O, μW, 160° C. 3.51

K₂CO₃, i-PrOH, H₂O, μW, 160° C. 3.52

TEA, DMSO 120° C. 3.53

TEA, DMSO 120° C. 3.54

TEA, DMSO 120° C.

TABLE 15C 1H NMR (PPM) DATA FOR EXAMPLES 3.1 TO 3.54 Ex. # Structure NMR3.1

(CD₃OD, 400 MHz): 8.11 (d, J = 2.4 Hz, 1H); 8.30 (d, J = 2.4 Hz, 1H);7.68-7.66 (m, 1H); 7.51- 7.49 (m, 1H); 7.37-7.33 (m, 1H); 7.29-7.25 (m,1H); 5.03-4.98 (m, 1H); 4.79-4.76 (m, 1H); 4.53- 4.49 (m, 1H); 4.41-4.39(m, 1H); 4.26-4.23 (m, 1H); 4.05 (s, 3 H); 3.03-3.00 (m, 4 H); 1.72-1.67 (m, 4H); 1.61-1.57 (m, 2 H). 3.2

(CD₃OD, 400 MHz): 8.17-8.16 (m, 1H); 8.10- 8.09 (m, 1H); 7.71-7.69 (m,1H); 7.58-7.55 (m, 1H); 7.41-7.39 (m, 1H); 7.37-7.29 (m, 1H); 5.04- 5.01(m, 1H); 4.79-4.76 (m, 1H); 4.57-4.54 (m, 1H); 4.46-4.45 (m, 1H);4.31-4.26 (m, 1H); 4.09 (s, 3 H); 3.38-3.34 (m, 1H); 2.95-2.89 (m, 2 H);1.99-1.97 (m, 2H); 1.69-1.67 (m, 2H). 3.3

(CD₃OD, 400 MHz): 8.14 (d, J = 2.4 Hz, 1H); 8.08 (d, J = 2.4 Hz, 1H);7.75-7.73 (m, 1H); 7.63- 7.61 (m, 1H); 7.44-7.40 (m, 1H); 7.36-7.33 (m,1H); 5.63-5.58 (m, 2 H); 5.12-5.07 (m, 1H); 4.92- 4.90 (m, 1H);4.54-4.52 (m, 1H); 4.44-4.40 (m, 1H); 4.31-4.28 (m, 1H); 3.06-3.03 (m,4H); 1.75- 1.69 (m, 4 H); 1.64-1.59 (m, 2H). 3.4

(CD₃OD, 400 MHz): 8.16 (d, J = 2.8 Hz, 1H); 8.09 (d, J = 2.8 Hz, 1H);7.76-7.74 (m, 1H); 7.64- 7.62 (m, 1H); 7.45-7.43 (m, 1H); 7.37-7.33 (m,1H); 5.64-5.58 (m, 2H); 5.10-5.08 (m, 1H); 4.93- 4.89 (m, 1H); 4.56-4.53(m, 1H); 4.45-4.41 (m, 1H); 4.38-4.31 (m, 1H); 3.78-3.76 (m, 4H); 3.38-3.36 (m, 2 H); 2.95-2.90 (m, 2H); 2.00-1.96 (m, 2H); 1.70-1.67 (m, 2H)3.5

(CDCl₃, 400 MHz): 7.98-7.96 (m, 2H); 7.74-7.64 (m, 2H); 7.31-7.26 (m,2H); 5.25-5.12 (m, 2H); 4.80-4.76 (m, 1H); 4.60-4.55 (m, 1H); 4.35-4.29(m, 1H); 3.51-3.49 (m, 4H); 2.04-1.99 (m, 4H). 3.6

(CDCl₃, 400 MHz): 8.21 (d, J = 2.4 Hz, 1H); 8.12 (d, J = 2.4, 1H); 7.67(br, 2H); 7.33-7.31 (m, 2H); 5.32-5.27 (m, 1H); 5.10-5.06 (m, 1H);4.63-4.61 (m, 2H); 4.30-4.26 (m, 1H); 3.45 (s, 2H); 2.93- 2.81 (m, 2H);2.26-2.19 (m, 1H); 1.99-1.98 (m, 2H); 1.87-1.74 (m, 2H). 3.7

(CDCl₃, 400 MHz): 8.26-8.23 (m, 2H); 7.73-7.71 (m, 2H); 7.38-7.35 (m,2H); 5.32-5.23 (m, 1H); 5.07-5.00 (m, 1H); 4.60-4.45 (m, 2H); 4.49-4.47(m, 3H); 3.51-3.48 (m, 1H); 3.12-3.08 (m, 1H); 3.03-2.91 (m, 1H);1.88-1.73 (m, 4H); 1.57-1.55 (m, 2H); 1.01-0.99 (m, 1H); 1.51-1.47 (m,3H) 3.8

(CDCl₃, 400 MHz): 8.10-8.04 (m, 2H); 7.75-7.74 (m, 1H); 7.51-7.50 (m,1H); 7.29-7.19 (m, 1H); 5.24-5.18 (m, 1H); 5.07-5.04 (m, 1H); 4.57-4.56(m, 2H); 4.25-4.21 (m, 1H); 3.25-3.22 (m, 2H); 2.75-2.70 (m, 1H);2.48-2.39 (m, 1H); 1.83-1.65 (m, 4H); 1.07-1.03 (m, 1H); 0.91 (d, J =6.4 Hz, 3H) 3.9

(CDCl₃, 400 MHz): 8.11-8.05 (m, 2H); 7.75-7.74 (m, 1H); 7.51-7.50 (m,1H); 7.25-7.19 (m, 2H); 5.26-5.21 (m, 1H); 5.07-5.04 (m, 1H); 4.57-4.56(m, 2H); 4.26-4.23 (m, 1H); 3.34-3.29 (m, 2 H); 2.78-2.74 (m, 2H);1.75-1.72 (m, 2H); 1.55-1.53 (m, 1H); 1.38-1.31 (m, 2 H); 0.97 (d, J =6.4 Hz, 3H). 3.10

(CDCl₃, 400 MHz): 8.14-8.10 (m, 2H); 7.70-7.68 (m, 2H); 7.32-7.24 (m,2H); 5.30-5.26 (m, 1H); 5.08-5.03 (m, 1H); 4.62-4.60 (m, 2H); 4.29-4.25(m, 1H); 3.10-3.08 (m, 4H); 1.55-1.53(m, 4H); 1.01 (s, 6H). 3.11

(CDCl₃, 400 MHz): 8.14-8.13 (m, 1H); 8.08-8.07 (m, 1H); 7.77-7.75 (m,1H); 7.55-7.52 (m, 1H); 7.30-7.22 (m, 2H); 5.27-5.21 (m, 1H); 5.07-5.04(m, 1H); 4.60-4.58 (m, 2H); 4.25-4.21 (m, 1H); 3.58-3.55 (m, 2H);3.40-3.34 (m, 2H); 2.89-2.77 (m, 2H); 2.41 (br, 1H); 1.87-1.84 (m, 1H);1.69- 1.68 (m, 1H); 1.49-1.40 (m, 2H). 3.12

(CD₃OD, 400 MHz): 8.16 (d, J = 2.4 Hz, 1H); 8.09 (d, J = 2.4 Hz, 1H);7.63 (brs, 2H); 7.30-7.28 (m, 2H); 5.20-5.16 (m, 1H); 4.98-4.93 (m, 1H);4.60-4.56 (m, 1H); 4.47-4.43 (m, 1H); 4.37-4.35 (m, 1H); 3.46(d, J =12.4 Hz, 2H); 2.83-2.78 (m, 2H); 1.89-1.86 (m, 2H); 1.56-1.46 (m, 3H);1.19 (s, 6H) 3.13

(CDCl₃, 400 MHz): 8.12 (d, J = 2.4 Hz, 1H); 8.04 (d, J = 2.4 Hz, 1H);7.79 (br, 1H); 7.51 (br, 1H); 7.19 (br, 2H); 5.25-5.20 (m, 1H);5.04-5.00 (m, 1H); 4.58-4.56 (m, 2H); 4.24-4.21 (m, 1H); 3.38- 3.35 (m,1H); 3.31 (s, 3H); 3.30-3.27 (m, 2H); 2.94-2.89 (m, 2H); 2.02-1.98 (m,2H); 1.73-1.68 (m, 2H). 3.14

(CDCl₃, 400 MHz): 8.20 (d, J = 42.4 Hz, 1H); 8.13 (d, J = 2.4 Hz, 1H);7.70-7.68 (m, 2H); 7.35- 7.32 (m, 2H); 5.32-5.27 (m, 1H); 5.03-4.99 (m,1H); 4.64-4.56 (m, 2H); 4.29-4.23 (m, 1H); 3.34- 3.29 (m, 2H); 3.09-3.02(m, 2H); 2.86-2.82 (m, 1H); 2.12-1.97 (m, 4H). 3.15

(CDCl₃, 400 MHz): 8.15-8.06 (m, 2H); 7.376-7.74 (m, 1H); 7.52-7.50 (m,1H); 7.28-7.24 (m, 2H); 5.27-5.22 (m, 1H); 5.07-5.04 (m, 1H); 4.61-4.58(m, 2H); 4.27-4.24 (m, 1H); 3.36-3.27 (m, 7H); 2.89-2.78 (m, 2H);1.92-1.78 (m, 3H); 1.49-1.40 (m, 2H). 3.16

(CDCl₃, 400 MHz): 7.95-7.93 (m, 2H); 7.67 (brs, 2H); 7.32-7.24 (m, 2H);5.25-5.12 (m, 2H); 4.72- 4.70 (m, 1H); 4.62-4.48 (m, 1H); 4.31-4.27 (m,1H); 3.63-3.48 (m, 3H); 3.19-3.12 (m, 1H); 2.34- 2.32 (m, 1H); 2.12-2.09(m, 1H); 1.61-1.58 (m, 1H); 1.14-1.12 (m, 3H). 3.17

(CDCl₃, 400 MHz): 7.98-7.96 (m, 2H); 7.75-7.59 (m, 2H); 7.26-7.24 (m,2H); 5.31-5.08 (m, 2H); 4.69-4.47 (m, 2H); 4.21-4.19 (m, 2H); 3.70-3.68(m, 1H); 3.13-3.11 (m, 1H); 2.16-2.15 (m, 1H); 1.95-1.94 (m, 1H);1.77-1.76 (m, 1H); 1.63-1.62 (m, 1H); 1.18 (s, 3H) 3.18

(CDCl₃, 400 MHz): 8.20-8.13 (m, 2H); 7.68 (brs, 2H); 7.33-7.32 (m, 2H);7.24-7.16 (m, 4H); 5.34- 5.29 (m, 1H); 5.15-5.11 (m, 1H); 4.68-4.59 (m,2H); 4.46-4.31 (m, 3H); 3.42-3.40 (m, 2H); 3.16- 3.05 (m, 2H). 3.19

(CDCl₃, 400 MHz): 8.07-8.06 (rn, 1H); 8.00-7.99 (m, 1H); 7.70-7.48 (m,1H); 7.39-7.37 (m, 2H); 7.29-7.17 (m, 4H); 5.07-5.05 (m, 1H); 5.00-4.90(m, 6H); 4.52-4.46 (m, 2H). 3.20

(CDCl₃, 400 MHz): 7.98-7.96 (m, 2H); 7.69-7.68 (m, 2H); 7.35-7.30 (m,4H); 7.28-7.15 (m, 3H); 5.27-5.23 (m, 1H); 5.13-5.07 (m, 1H); 4.67-4.63(m, 1H); 4.55-4.43 (m, 1H); 4.34-4.32 (m, 1H); 3.83-3.75 (m, 2H);3.70-3.65 (m, 2H); 3.48-3.46 (m, 1H); 2.41-2.39 (m, 1H); 2.14-2.12 (m,1H). 3.21

(CDCl₃, 400 MHz): 7.93-7.89 (m, 2H); 7.67 (brs, 2H); 7.50-7.24 (m, 6H);7.17-7.15 (m, 1H); 5.23- 5.05 (m, 3H); 4.65-4.63 (m, 1H); 4.53-4.51 (m,1H); 4.27-4.26 (m, 1H); 3.97-3.95 (m, 1H); 3.42- 3.40 (m, 1H); 2.42-2.41(m, 1H); 2.07-2.06 (m, 1H); 2.00-1.84 (m, 2H). 3.22

(CDCl₃, 400 MHz): 7.98 (d, J = 2.8 Hz, 1H); 7.80 (d, J = 2.8 Hz, 1H);7.69 (brs, 2H); 7.34-7.30 (m, 2H); 5.31-5.26 (m, 1H); 5.16-5.12 (m, 1H);4.78- 4.74 (m, 1H); 4.65-4.60 (m, 1H); 4.35-4.33 (m, 1H); 4.11-4.10 (m,1H); 3.95-3.88 (m, 1H); 2.17- 2.09 (m, 2H); 1.79-1.66 (m, 4H); 1.51-1.43(m, 2H). 3.23

(CDCl₃, 400 MHz): 7.89-7.72 (m, 2H); 7.62 (brs, 2H); 7.30-7.26 (m, 2H);5.25-5.20 (m, 1H); 5.11- 5.08 (m, 1H); 4.66-4.53 (m, 2H); 3.95-3.84 (m,2H); 2.02-1.99 (m, 1H); 1.73-1.35 (m, 6H); 1.21- 1.16 (m, 3H). 3.24

(CD₃OD, 400 MHz): 7.83-7.81 (m, 2H); 7.70-7.68 (m, 2H); 7.39-7.21 (m,7H); 5.19-5.13 (m, 1H); 5.10-5.06 (m, 1H); 4.67 (s, 2H); 4.63-4.54 (m,2H); 4.25-4.21 (m, 1H). 3.25

(CD₃OD, 400 MHz): 7.89-7.88 (m, 1H); 7.80- 7.79 (m, 1H); 7.69-7.66 (m,2H); 7.37-7.35 (m, 2H); 5.19-5.18 (m, 1H); 5.06-5.08 (m, 1H); 4.62- 4.55(m, 2H); 4.24-4.20 (m, 1H); 3.80-3.79 (m, 2H); 3.63-3.61 (m, 2 H). 3.26

(CDCl₃, 400 MHz): 7.94 (d, J = 2.4 Hz, 1H); 7.82 (d, J = 2.4 Hz, 1H);7.78-7.60 (m, 2H); 7.32-7.31 (m, 2H); 5.29-5.28 (m, 1H); 5.16-5.14 (m,1H); 4.76-4.73 (m, 2H); 4.65-4.63 (m, 1H); 4.00-3.95 (m, 1H); 3.71-3.61(m, 4H); 3.43 (s, 3H). 3.27

(CDCl₃, 400 MHz): 8.22-8.16 (m, 2 H); 7.65 (br, 2H); 7.62-7.54 (m, 4H);5.11-5.07 (m, 1H); 4.89- 4.85 (m, 1H); 4.51-4.49 (m, 1H); 4.29-4.25 (m,2H); 3.45-3.43 (m, 2 H); 2.83-2.73 (m, 1H); 2.52- 2.51 (m, 1H);1.82-1.71 (m, 4 H). 3.28

(CD₃OD, 400 MHz): 8.18 (d, J = 2.4 Hz, 1H); 8.11 (d, J = 2.4 Hz, 1H);7.68-7.65 (m, 2H); 7.35- 7.32 (m, 2H); 5.21-5.17 (m, 1H); 5.02-4.95 (m,1H); 4.65-4.59 (m, 1H); 4.47-4.36 (m, 2H); 3.57- 3.53 (m, 1H); 3.48-3.34(m, 3H); 2.86-2.84 (m, 1H); 2.64-2.58 (m, 1H); 1.96-1.94 (m, 1H); 1.85-1.76 (m, 3H); 1.21-1.18 (m, 1H). 3.29

(CD₃OD, 400 MHz): 8.17 (d, J = 2.4 Hz, 1H); 8.10 (d, J = 2.4 Hz, 1H);7.63 (brs, 2H); 7.28-7.20 (m, 2H); 5.20-5.14 (m, 1H); 4.97-4.92 (m, 1H);4.58-4.53 (m, 1H); 4.47-4.42 (m, 1H); 4.38-4.32 (m, 1H); 3.89-3.85 (m,1H); 3.41-3.37 (m, 1H); 3.34-3.20 (m, 1H); 2.88-2.77 (m, 2H); 2.02-1.98(m, 1H); 1.91-1.88 (m, 1H); 1.71-1.67 (m, 1H); 1.49-1.46 (m, 1H). 3.30

(CDCl₃, 400 MHz): 8.04-8.00 (m, 2H); 7.73-7.70 (m, 2H); 7.38-7.36 (m,2H); 5.27-5.22 (m, 1H); 5.03-4.99 (m, 1H); 4.60-4.53 (m, 2H); 4.27-4.23(m, 1H); 3.45-3.42 (m, 4H); 1.83 (brs, 4H) 1.65- 1.63 (m, 6H). 3.31

(CD₃OD, 400 MHz): 7.97-7.92 (m, 2H); 7.76-7.74 (m, 1H); 7.59-7.58 (m,1H); 7.32 (br, 2H); 5.15- 5.13 (m, 1H); 5.04-5.01 (m, 1H); 4.57-4.50 (m,2 H); 4.20-4.14 (m, 5H); 2.45-2.37 (m, 1H). 3.32

(CDCl₃, 400 MHz): 7.97-7.94 (m, 1H); 7.84-7.81 (m, 1H); 7.71-7.65 (m,2H); 7.22 (brs, 2H); 5.27- 5.23 (m, 1H); 5.01 -5.02 (m, 1H); 4.62-4.56(m, 2H); 4.39-4.36 (m, 1H); 4.20-4.15 (m, 1H); 3.77- 3.60 (m, 3H);3.20-3.15 (m, 1H); 2.09 (s, 3H); 1.95-1.92 (m, 1H); 1.77-1.75 (m, 2 H).3.33

(CD₃OD, 400 MHz): 7.88-7.81 (m, 2H); 7.68-7.66 (m, 2H); 7.35-7.33 (m,2H); 5.20-5.15 (m, 1H); 5.03-4.99 (m, 1H); 4.62-4.50 (m, 2H); 4.28-4.17(m, 1H); 4.15-4.10 (m, 1H); 1.33-1.30 (m, 6H). 3.34

(CDCl₃, 400 MHz): 7.96-7.94 (m, 1H); 7.83-7.81 (m, 1H); 7.70-7.60 (m,2H); 7.22 (brs, 2H); 5.26- 5.24 (m, 1H); 5.011-5.02 (m, 1H); 4.61-4.56(m, 2H); 4.38-4.36 (m, 1H); 4.18-4.16 (m, 1H); 3.76- 3.59 (m, 3H);3.15-3.13 (m, 1H); 2.08 (s, 3H); 1.94-1.92 (m, 1H); 1.76-1.73 (m, 2 H).3.35

(CDCl₃, 400 MHz): 8.20-8.17 (m, 2H); 7.75-7.72 (m, 2 H); 7.43-7.40 (m,2H); 5.33-5.32 (m, 1H); 505-5.02 (m, 1H); 4.63-4.61 (m, 2H); 4.57-4.55(m, 1H); 4.36-4.34 (m, 1H); 3.79-3.77 (m, 1H); 3.42-3.36 (m, 2H);2.95-2.90 (m, 2 H); 1.89-1.79 (m, 3 H); 1.65-1.67 (m, 2 H); 1.47-1.45(m, 2H). 3.36

(CD₃OD, 400 MHz): 8.11-8.06 (m, 2 H); 7.72- 7.70 (m, 2H); 7.43-7.40 (m,2H); 5.16-5.11 (m, 1H); 5.00-4.98 (m, 1H); 4.59-4.52 (m, 2H); 4.34- 4.33(m, 1H); 3.89-3.82 (m, 4H); 2.06-2.03 (m, 2H). 3.37

(CD₃OD, 400 MHz): 8.17-8.16 (m, 1H); 8.08- 8.07 (m, 1H); 7.68-7.66 (m,2H); 7.36-7.34 (m, 2H); 5.17-5.14 (m, 1H); 4.95-4.94 (m, 1H); 4.59- 4.52(m, 2H); 4.35-4.27 (m, 1H); 3.76-3.57 (m, 6H); 3.37-3.31 (m, 2H); 3.30(s, 3H); 2.26-2.24 (m, 2 H). 3.38

(CDCl₃, 400 MHz): 8.13-8.07 (m, 2H); 7.73-7.70 (m, 2H); 7.44-7.41 (m,2H); 5.12-5.09 (m, 1H); 4.95-4.94 (m, 1H); 4.62-4.51 (m, 2H); 4.33-4.30(m, 1H); 3.79-3.76 (m, 2H); 3.66-3.60 (m, 3H); 3.48-3.45 (m, 2H);3.42-3.40 (m, 1H); 2.11 (s, 3H); 2.05-2.02 (m, 1H); 1.94-1.88 (m, 1H).3.39

(CD₃OD, 400 MHz): 8.05-8.00 (m, 2 H); 7.70- 7.68 (m, 2H); 7.39-7.36 (m,2H); 5.15-5.13 (m, 1H); 4.99-4.98 (m, 1H); 4.56-4.50 (m, 2H); 4.33- 4.30(m, 1H); 3.92-3.90 (m, 1H); 3.57-3.54 (m, 1H); 3.47-3.41 (m, 3H);2.14-2.11 (m, 1H); 1.99- 1.69 (m, 5H). 3.40

(CD₃OD, 400 MHz): 7.98-7.97 (m, 1H); 7.88- 7.87 (m, 1H); 7.69-7.66 (m,2H); 7.37-7.34 (m, 2H); 5.15-5.07 (m, 1H); 4.58-4.44 (m, 2H); 3.66- 3.60(m, 5H); 3.45-3.43 (m, 1H); 3.65 (s, 2H); 2.55-2.51 (m, 1H); 2.16-2.11(m, 1H); 1.85-1.80 (m, 1H). 3.41

(CDCl₃, 400 MHz): 8.19 (d, J = 2.8 Hz, 1H); 8.11 (d, J = 2.8, 1H);7.67-7.64 (m, 2H); 7.33-7.30 (m, 2H); 5.20-5.18 (m, 1H); 4.98-4.96 (m,1H); 4.58- 4.56 (m, 1H); 4.48-4.45 (m, 1H); 4.40-4.38 (m, 1H); 3.89-3.86(m, 1H); 3.42-3.39 (m, 1H); 3.22- 3.18 (m, 1H); 2.90-2.89 (m, 1H);2.84-2.80 (m, 1H); 2.02-2.00 (m, 1H); 1.93-1.90 (m, 1H); 1.74- 1.70 (m,1H); 1.50-1.48 (m, 1H). 3.42

(CDCl₃, 400 MHz): 8.20 (d, J = 2.8 Hz, 1H); 8.12 (d, J = 2.8, 1H); 7.66(br, 2H); 7.34-7.31 (m, 2H); 5.21-5.19 (m, 1H); 4.97-4.96 (m, 1H);4.61-4.54 (m, 1H); 4.48-4.38 (m, 2H); 3.89-3.85 (m, 1H); 3.42-3.41 (m,1H); 3.23-3.20 (m, 1H); 2.91-2.88 (m, 1H); 2.84-2.79 (m, 1H); 2.04-2.00(m, 1H); 1.95-1.90 (m, 1H); 1.74-1.70 (m, 1H); 1.51-1.47 (m, 1H). 3.43

(CDCl₃, 400 MHz): 8.22 (m, 1H); 8.11 (m, 1H); 7.68-7.65 (m, 2H);7.35-7.31 (m, 2H); 5.30 (m, 1H); 5.02 (m, 1H); 4.60 (d, J = 6.4 Hz, 2H);4.37- 4.34 (m, 1H); 3.34-3.28 (m, 2H); 3.08-2.93 (m, 3H); 1.98-1.90 (m,3H); 1.74-1.72 (m, 1H). 3.44

(CDCl₃, 400 MHz): 8.18 (d, J = 2.0 Hz, 1H); 8.12 (d, J = 2.4 Hz, 1H);7.74-7.71 (m, 2H); 7.40-7.38 (m, 2H); 5.31 (t, J = 9.6 Hz, 1H);5.04-5.00 (m, 1H); 4.62-4.58 (m, 2H); 4.34-4.27 (m, 1H); 3.40 (t, J =12.0 Hz, 2H); 2.91 (d, J = 12.8 Hz, 1H); 2.86 (d, J = 4.4 Hz, 4H);2.37-2.31 (m, 1H); 2.07- 1.87 (m, 4H). 3.45

(CDCl₃, 400 MHz): 8.14 (d, J = 2.4 Hz, 1H); 8.07 (d, J = 2.8 Hz, 1H);7.67-7.65 (m, 2H); 5.22 (t, J = 10.0 Hz, 1H); 5.03-4.99 (m, 1H); 4.54(d, J = 7.2 Hz, 2H); 4.28-4.24 (m, 1H); 3.37 (t, J = 12.8 Hz, 2H); 3.07(s, 3H); 2.94 (s, 3H); 2.92-2.80 (m, 2H); 2.71-2.65 (m, 1H); 2.02-1.93(m, 2H); 1.80 (d, J = 8.4 Hz, 2H). 3.46

(CDCl₃, 400 MHz): 8.15-8.14 (m, 1H); 8.06-8.05 (m, 1H); 7.07-7.06 (m,1H); 7.47-7.46 (m, 1H); 7.28-7.18 (m, 2H); 5.23-5.21 (m, 1H); 5.04-5.02(m, 1H); 4.56-5.54 (m, 2H); 4.23-4.21 (m, 1H); 3.38-3.36 (m, 2H);2.89-2.80 (m, 2H); 2.48-2.45 (m, 1H); 2.16 (s, 3H); 1.98-1.96 (m, 2H);1.82- 1.79 (m, 2H). 3.47

(CDCl₃, 400 MHz): 8.20 (d, J = 2.4 Hz, 1H); 8.10 (d, J = 2.4 Hz, 1H);7.66-7.64 (m, 2H); 7.32-7.29 (m, 2H); 5.26 (t, J = 8.0 Hz, 1H);5.03-5.00 (m, 1H); 4.60-4.54 (m, 2H); 4.28-4.25 (m, 1H); 3.81- 3.71 (m,2H); 3.63-3.61 (m, 2H); 3.15-3.14 (m, 2H); 3.07-3.05 (m, 2H); 2.14 (s,3H). 3.48

(MeOD, 400 MHz): 8.00-7.97 (m, 1H); 7.92-7.88 (m, 1H); 7.68 (brs, 2H);7.36-7.35 (m, 2H); 5.18- 5.05 (m, 2H); 4.61-4.46 (m, 4H); 3.87-3.79 (m,2H); 3.56-3.52 (m, 1H); 3.41-3.39 (m, 1H); 2.13- 1.93 (m, 2H). 3.49

(MeOD, 400 MHz): 7.96-7.92 (m, 1H); 7.91-7.89 (m, 1H); 7.68 (brs, 2H);7.35-7.33 (m, 2H); 5.21- 4.88 (m, 2H); 4.63-4.41 (m, 4H); 3.86-3.80 (m,2H); 3.55-3.50 (m, 1H); 3.37-3.40 (m, 1H); 2.13- 2.00 (m, 2H). 3.50

(CDCl₃, 400 MHz): 8.16 (d, J = 2.4 Hz, 1H); 8.11 (d, J = 2.4 Hz, 1H);7.71-7.69 (m, 2H); 7.32-7.30 (m, 2H); 5.33-5.28 (m, 1H); 5.11-5.07 (m,1H); 4.67-4.65 (m, 2H); 4.32-4.29 (m, 1H); 3.11-3.08 (m, 4H); 1.78-1.74(m, 4H); 1.68-1.64 (m, 2H). 3.51

(MeOD, 400 MHz): 8.17 (d, J = 2.8 Hz, 1H); 8.10 (d, J = 2.8 Hz, 1H);7.71-7.68 (m, 2H); 7.42- 7.39 (m, 2H); 5.13-5.15 (m, 1H); 4.94-4.93 (m,1H); 4.61-4.59 (m, 1H); 4.46-4.50 (m, 1H); 4.39- 4.35 (m, 1H); 3.80-3.76(m, 1H); 3.39-3.35 (m, 2H); 2.98-2.92 (m, 2H); 2.01-1.97 (m, 2H); 1.71-1.68 (m, 2H). 3.52

(CDCl₃, 400 MHz): 8.19 (d, J = 2.4 Hz, 1H), 8.10 (d, J = 2.4 Hz, 1H),7.81-7.65 (m, 1H), 7.56-7.50 (m, 1H), 7.32 (s, 2H), 5.30-5.24 (m, 1H),5.09- 5.05 (m, 1H), 4.61 (d, J = 16 Hz, 2H), 4.49 (s, 4H), 4.32-4.24 (m,1H), 3.04-3.01 (m, 4H), 2.07- 2.03 (m, 4H). 3.53

(CDCl₃, 400 MHz): 8.00 (d, J = 4.0 Hz, 2H), 7.76-7.59 (m, 2H), 7.31-7.29(m, 2H), 5.24-5.19 (m, 1H), 5.12-5.08 (m, 1H), 4.87 (s, 4H), 4.81- 7.76(m, 1H), 4.61-4.54 (m, 1H), 4.27 (s, 4H), 4.04-4.00 (m, 1H) 3.54

(MeOD, 400 MHz): 7.99 (dd, J = 2.8 Hz, 7.6 Hz, 2H), 7.66-7.62 (m, 2H),7.33-7.30 (m, 2H), 5.17- 5.12 (m, 1H), 5.02-4.98 (m, 1H), 4.61-4.50 (m,2H), 4.41 (s, 2H), 4.28 (s, 4H), 4.19-4.12 (m, 3H), 1.88 (s, 3H).

Example 4.12-(3-(3-(2-METHOXYPYRIDIN-3-YL)PYRAZIN-2-YL)AZETIDIN-1-YL)QUINOLINE

A glass microwave reaction vessel was charged with2-(3-(3-chloropyrazin-2-yl)azetidin-1-yl)quinoline (0.160 g, 0.539mmol), sodium carbonate (0.300 g, 2.83 mmol, JT Baker),2-methoxy-3-pyridineboronic acid (0.150 g, 0.981 mmol, Aldrich) andtrans-dichlorobis(triphenylphosphine)palladium (ii) (0.030 g, 0.043mmol, Strem). Dioxane (3 mL) and water (1 mL) were added and thereaction mixture was sealed under argon and heated in an Initiatormicrowave reactor (Personal Chemistry, Biotage AB, Inc., Upssala,Sweden) at 145° C. for 15 min. The reaction mixture was partitionedbetween EtOAc/water and the aqueous layer was extracted with EtOAc (3×).The combined organic layers were evaporated to dryness and the residuewas dissolved in MeOH and purified by reverse-phase HPLC (Gilson;Gemini-NX 10 m C18 110A AXIA, 100×50 mm column) eluting with 0.1%TFA-H₂O:0.1% TFA CH₃CN (9:1→1:9). The fractions containing the desiredproduct were combined and concentrated in vacuo. The residue wasdissolved in MeOH and loaded onto an SCX II cartridge eluting with MeOHthen 2M NH₃ in MeOH to give 145 mg (73%) of an off-white amorphoussolid.

The following Table 16A lists compounds of Examples 4.1 to 4.45, whichwere made analogous to Scheme 4 by using the appropriate materials andreaction conditions, which are listed in Table 16B. The NMR data of theExamples are listed in Table 16C.

TABLE 16A EXAMPLES 4.1 TO 4.45 ESI-MS IC₅₀ Ex. # Structure Chemical Name(M + 1) (nM) 4.1

2-(3-(3-(2-methoxypyridin-3- yl)pyrazin-2-yl)azetidin-1- yl)quinoline370.0 0.00234 4.2

2-(3-(3-(6-methylpyridin-3- yl)pyrazin-2-yl)azetidin-1- yl)quinoline 3540.00279 4.3

2-(3-(3-(2-methylpyridin-3- yl)pyrazin-2-yl)azetidin-1- yl)quinoline354.20 0.00648 4.4

2-(3-(3-(6-fluoropyridin-3- yl)pyrazin-2-yl)azetidin-1- yl)quinoline358.0 0.00418 4.5

2-(3-(3-(6- (trifluoromethyl)pyridin-3- yl)pyrazin-2-yl)azetidin-1-yl)quinoline 408.0 0.0142 4.6

2-(3-(3-(2,6-dimethoxypyridin- 3-yl)pyrazin-2-yl)azetidin-1-yl)quinoline 400.20 0.00135 4.7

2-(3-(3-(5-fluoropyridin-3- yl)pyrazin-2-yl)azetidin-1- yl)quinoline358.20 0.0123 4.8

2-(3-(3-(6-methoxypyridin-3- yl)pyrazin-2-yl)azetidin-1- yl)quinoline2,2,2- trifluoroacetate 370.2 0.00787 4.9

2-(3-(3-(6-fluoro-5- methylpyridin-3-yl)pyrazin-2-yl)azetidin-1-yl)quinoline 2,2,2-trifluoroacetate 372.20 0.0122 4.10

2-(3-(3-(pyridin-3-yl)pyrazin-2- yl)azetidin-1-yl)quinoline 2,2,2-trifluoroacetate 340.20 0.00787 4.11

2-(3-(3-(4- (methylsulfonyl)phenyl)pyrazin- 2-yl)azetidin-1-yl)quinoline417.2 0.00262 4.12

2,2,2-trifluoroacetatc 5-(3-(1-(quinolin-2-yl)azetidin-3-yl)pyrazin-2-yl)pyridin-2- amine 355.20 0.00278 4.13

5-(3-(1-(quinolin-2-yl)azetidin- 3-yl)pyrazin-2-yl)pyridin-3- amine355.0 0.00376 4.14

2-(3-(3-(6-methoxypyridin-2- yl)pyrazin-2-yl)azetidin-1- yl)quinoline370.20 0.0012 4.15

2-(3-(3-(2- (trifluoromethyl)pyridin-3- yl)pyrazin-2-yl)azetidin-1-yl)quinoline 2,2,2- trifluoroacetate 408.0 0.12360 4.16

N,N-dimethyl-5-(3-(1-(quinolin- 2-yl)azetidin-3-yl)pyrazin-2-yl)pyrimidin-2-amine 2,2,2- trifluoroacetate 384.0 0.02279 4.17

2-(3-(3-(4-methylpyridin-3- yl)pyrazin-2-yl)azetidin-1- yl)quinoline2,2,2- trifluoroacetate 354.0 0.02626 4.18

2-(3-(3-(2- (methylsulfonyl)pyridin-3- yl)pyrazin-2-yl)azetidin-1-yl)quinoline 2,2,2- trifluoroacetate 418.0 4.19

2-(3-(3-(5-methylpyridin-3- yl)pyrazin-2-yl)azetidin-1- yl)quinoline2,2,2- trifluoroacetate 354.0 0.01625 4.20

2-(3-(3-(5-methoxypyridin-3- yl)pyrazin-2-yl)azetidin-1- yl)quinoline2,2,2- trifluoroacetate 370.1 0.02472 4.21

2-(3-(3-(4-chloro-3- methylphenyl)pyrazin-2- yl)azetidin-1-yl)quinoline387.1 0.0023 4.22

2-(3-(3-(3-fluoro-4- methylphenyl)pyrazin-2- yl)azetidin-1-yl)quinoline371.2 0.0042 4.23

2-chloro-4-(3-(1-(quinolin-2- yl)azetidin-3-yl)pyrazin-2- yl)phenol389.0 0.0023 4.24

2-(3-(3-(3-methoxy-5- (trifluoromethyl)phenyl)pyrazin-2-yl)azetidin-1-yl)quinoline 437.2 0.0149 4.25

2-(3-(3-(4-ethoxy-3- fluorophenyl)pyrazin-2- yl)azetidin-1-yl)quinoline401.2 0.0062 4.26

2-(3-(3-(3-chloro-4- ethoxyphenyl)pyrazin-2- yl)azetidin-1-yl)quinoline417.00 0.0106 4.27

2-(3-(3-(3-chloro-4- propoxyphenyl)pyrazin-2- yl)azetidin-1-yl)quinoline432.2 0.0171 4.28

2-(3-(3-(3-fluoro-5- (trifluoromethyl)phenyl)pyrazin-2-yl)azetidin-1-yl)quinoline 425.20 0.0122 4.29

2-(3-(3-(4-methoxy-3- methylphenyl)pyrazin-2- yl)azetidin-1-yl)quinoline383.20 0.0035 4.30

2-(3-(3-(3-fluoro-5- isopropoxyphenyl)pyrazin-2-yl)azetidin-1-yl)quinoline 415.20 0.0110 4.31

2-(3-(3-(3-fluoro-5- methylphenyl)pyrazin-2- yl)azetidin-1-yl)quinoline371.20 0.0051 4.32

2-(3-(3-(3-chloro-4- fluorophenyl)pyrazin-2- yl)azetidin-1-yl)quinoline392.20 0.0041 4.33

2-(3-(3-(3,4- difluorophenyl)pyrazin-2- yl)azetidin-1-yl)quinoline375.20 0.0099 4.34

2-(3-(3-(3,4- dichlorophenyl)pyrazin-2- yl)azetidin-1-yl)quinoline 407.00.0084 4.35

2-(3-(3-(3,4- dimethylphenyl)pyrazin-2- yl)azetidin-1-yl)quinoline367.20 0.0055 4.36

2-(3-(3-(3-chloro-4- methylphenyl)pyrazin-2- yl)azetidin-1-yl)quinoline388.2 0.0067 4.37

2-(3-(3-(3-chloro-5- methylphenyl)pyrazin-2- yl)azetidin-1-yl)quinoline387.0 0.0072 4.38

2-(3-(3-(4-fluoro-3- methylphenyl)pyrazin-2- yl)azetidin-1-yl)quinoline371.0 0.0064 4.39

2-(3-(3-(pyrimidin-5-yl)pyrazin- 2-yl)azetidin-1-yl)quinoline 341.200.0887 4.40

2-(3-(3-(4-chloro-3- (trifluoromethyl)phenyl)pyrazin-2-yl)azetidin-1-yl)quinoline 441.0 0.0091 4.41

2-(3-(3-(3,6-dihydro-2H-pyran- 4-yl)pyrazin-2-yl)azetidin-1-yl)quinoline 345 0.0011 4.42

2-(3-(3-(2,2-dimethyl-3,6- dihydro-2H-pyran-4-yl)pyrazin-2-yl)azetidin-1-yl)quinoline and 2-(3-(3-(6,6-dimethyl-3,6-dihydro-2H-pyran-4-yl)pyrazin- 2-yl)azetidin-1-yl)quinoline 373 0.0014.43

2-(3-(3-(1H-pyrazol-4- yl)pyrazin-2-yl)azetidin-1- yl)quinoline 3290.007 4.44

2-(3-(3-(3-fluoro-5- (trifluoromethyl)phenyl)pyrazin-2-yl)azetidin-1-yl)quinoline 425.20 0.0122 4.45

2-(3-(3-(6-methoxypyridin-2- yl)pyrazin-2-yl)azetidin-1- yl)quinoline370.20 0.0012

TABLE 16B STARTING MATERIALS AND REACTION CONDITION FOR PREPARATION OFEXAMPLES 4.1 TO 4.45. Reaction Purification Ex. # Key Starting Material(s) Key Starting Material (s) Condition Method* 4.1

PdCl₂(PPh₃)₂, Na₂CO₃ Dioxane/water, 145° C., μW A 4.2

PdCl₂(PPh₃)₂, Na₂CO₃ Dioxane/water, 145° C., μW A 4.3

PdCl₂(PPh₃)₂, Na₂CO₃ Dioxane/water, 145° C., μW B 4.4

PdCl₂(PPh₃)₂, Na₂CO₃ Dioxane/water, 145° C., μW B 4.5

PdCl₂(PPh₃)₂, Na₂CO₃ Dioxane/water, 145° C., μW B 4.6

PdCl₂(PPh₃)₂, Na₂CO₃ Dioxane/water, 145° C., μW B 4.7

PdCl₂(PPh₃)₂, Na₂CO₃ Dioxane/water, 145° C., μW B 4.8

PdCl₂(PPh₃)₂, Na₂CO₃ Dioxane/water, 145° C., μW E 4.9

PdCl₂(PPh₃)₂, Na₂CO₃ Dioxane/water, 145° C., μW E 4.10

PdCl₂(PPh₃)₂, Na₂CO₃ Dioxane/water, 145° C., μW E 4.11

PdCl₂(PPh₃)₂, Na₂CO₃ Dioxane/water, 145° C., μW E 4.12

PdCl₂(PPh₃)₂, Na₂CO₃ Dioxane/water, 145° C., μW D 4.13

PdCl₂(PPh₃)₂, Na₂CO₃ Dioxane/water, 145° C., μW D 4.14

PdCl₂(PPh₃)₂, Na₂CO₃ Dioxane/water, 145° C., μW D 4.15

PdCl₂(PPh₃)₂, Na₂CO₃ Dioxane/water, 145° C., μW C 4.16

PdCl₂(PPh₃)₂, Na₂CO₃ Dioxane/water, 145° C., μW C 4.17

PdCl₂(PPh₃)₂, Na₂CO₃ Dioxane/water, 145° C., μW C 4.18

PdCl₂(PPh₃)₂, Na₂CO₃ Dioxane/water, 145° C., μW C 4.19

PdCl₂(PPh₃)₂, Na₂CO₃ Dioxane/water, 145° C., μW C 4.20

PdCl₂(PPh₃)₂, Na₂CO₃ Dioxane/water, 145° C., μW C 4.21

PdCl₂(PPh₃)₂, Na₂CO₃ Dioxane/water, 145° C., μW D 4.22

PdCl₂(PPh₃)₂, Na₂CO₃ Dioxane/water, 145° C., μW D 4.23

PdCl₂(PPh₃)₂, Na₂CO₃ Dioxane/water, 145° C., μW D 4.24

PdCl₂(PPh₃)₂, Na₂CO₃ Dioxane/water, 145° C., μW D 4.25

PdCl₂(PPh₃)₂, Na₂CO₃ Dioxane/water, 145° C., μW D 4.26

PdCl₂(PPh₃)₂, Na₂CO₃ Dioxane/water, 145° C., μW D 4.27

PdCl₂(PPh₃)₂, Na₂CO₃ Dioxane/water, 145° C., μW D 4.28

PdCl₂(PPh₃)₂, Na₂CO₃ Dioxane/water, 145° C., μW D 4.29

PdCl₂(PPh₃)₂, Na₂CO₃ Dioxane/water, 145° C., μW D 4.30

PdCl₂(PPh₃)₂, Na₂CO₃ Dioxane/water, 145° C., μW D 4.31

PdCl₂(PPh₃)₂, Na₂CO₃ Dioxane/water, 145° C., μW D 4.32

PdCl₂(PPh₃)₂, Na₂CO₃ Dioxane/water, 145° C., μW D 4.33

PdCl₂(PPh₃)₂, Na₂CO₃ Dioxane/water, 145° C., μW D 4.34

PdCl₂(PPh₃)₂, Na₂CO₃ Dioxane/water, 145° C., μW D 4.35

PdCl₂(PPh₃)₂, Na₂CO₃ Dioxane/water, 145° C., μW D 4.36

PdCl₂(PPh₃)₂, Na₂CO₃ Dioxane/water, 145° C., μW D 4.37

PdCl₂(PPh₃)₂, Na₂CO₃ Dioxane/water, 145° C., μW D 4.38

PdCl₂(PPh₃)₂, Na₂CO₃ Dioxane/water, 145° C., μW D 4.39

PdCl₂(PPh₃)₂, Na₂CO₃ Dioxane/water, 145° C., μW D 4.40

PdCl₂(PPh₃)₂, Na₂CO₃ Dioxane/water, 145° C., μW D 4.41

Pd(tBu₃P)₂, KOAc Dioxane/water, 125° C./μW, 30 min E 4.42

Pd(tBu₃P)₂, KOAc Dioxane/water, 135° C./μW, 30 min E 4.43

Pd(tBu₃P)₂, KOAc Dioxane/water, 135° C./μW, 30 min F 4.44

PdCl₂(PPh₃)₂, Na₂CO₃ Dioxane/water, 145° C., μW D 4.45

PdCl₂(PPh₃)₂, Na₂CO₃ Dioxane/water, 145° C., μW D Unless otherwisestated, all starting materials are commercially available from commonvendors. *Purification Methods: Method A- reverse-phase HPLC (Gilson;Gemini-NX 10 m C18 110A AXIA, 100 × 50 mm column) eluting with 0.1%TFA-H₂O: 0.1% TFA CH₃CN (9:1 → 1:9). The fractions containing thedesired product were combined and concentrated in vacuo. The residue wasdissolved in MeOH and loaded onto an SCX II cartridge eluting with MeOHthen 2M NH₃ in MeOH. Method B- reverse-phase HPLC (Instrumentation:MS-Waters SQ; UV-Waters 2487 or Waters PD; Solvents: A: Water w/0.1%NH₄OH B: Acetonitrile w/0.1% NH₄OH; Column: Phenomenex Gemini-NX C18110A 5 um 21 × 100; Flow Rate: 44 mL/min. 10 min Method, variablegradient over 8 mins. Method C- reverse-phase HPLC (Gilson; Gemini-NX 10m C18 110A AXIA, 100 × 50 mm column) eluting with 0.1% TFA-H₂O: 0.1% TFACH₃CN (9:1 → 1:9). The fractions containing the desired product werecombined and concentrated in vacuo. Method D- reverse-phase HPLC(Instrument: Waters Autopurificaton system; Column: Xbridge 19 × 100 mm,10 um; Flow rate: 40 ml/min; Mobile phase: 0.1% NH₄OH in acetonitrile(B) and water (A)). Method E- reverse-phase HPLC (Instrument: WatersAutopurificaton system; Column: Xbridge 19 × 100 mm, 10 um; Flow rate:40 ml/min; Mobile phase: 0.1% TFA in acetonitrile (B) and water (A)).Method E- purification by silica gel chromatography eluting with agradient of EtOAc in hexane. Method F- purification by silica gelchromatography eluting with a gradient of MeOH in DCM.

TABLE 16C 1H NMR δ (PPM) DATA FOR EXAMPLES 4.1 TO 4.45 Ex. # StructureNMR 4.1

(300 MHz, DMSO-d₆) 2.69(s, 3 H) 4.21-4.50(m, 5 H) 6.75(d, J = 8.77 Hz, 1H) 7.21(ddd, J = 8.00, 6.47, 1.61 Hz, 1 H) 7.45(d, J = 8.04 Hz, 1 H)7.48-7.60(m, 2 H) 7.70(d, J = 7.60 Hz, 1 H) 7.93(dd, J = 7.97, 2.41 Hz,1 H) 8.02(d, J = 8.77 Hz, 1 H) 8.63-8.74(m, 3 H). 4.2

(300 MHz, DMSO-d₆) 2.59(s, 3 H) 4.21-4.50(m, 5 H) 6.75(d, J = 8.77 Hz, 1H) 7.21(ddd, J = 8.00, 6.47, 1.61 Hz, 1 H) 7.45(d, J = 8.04 Hz, 1 H)7.48-7.60(m, 2 H) 7.70(d, J = 7.60 Hz, 1 H) 7.93(dd, J = 7.97, 2.41 Hz,1 H) 8.02(d, J = 8.77 Hz, 1 H) 8.63-8.74(m, 3 H) 4.3

(400 MHz, DMSO-d₆) 8.74(d, J = 2.35 Hz, 1 H) 8.67(d, J = 2.35 Hz, 1 H)8.61(dd, J = 4.69, 1.56 Hz, 1 H) 8.02(d, J = 9.00 Hz, 1 H) 7.66-7.78 (m,2 H) 7.47-7.58(m, 2 H) 7.41 (dd, J = 7.63, 4.89 Hz, 1 H) 7.21(t, J =7.24 Hz, 1 H) 6.74(d, J = 8.61 Hz, 1 H) 4.24-4.31(m, 2 H) 4.17-4.24 (m,2 H) 3.93-4.07(m, 1 H) 2.28 (s, 3 H). 4.4

(400 MHz, DMSO-d₆) 8.74(d, J = 2.35 Hz, 1 H) 8.68(d, J = 2.35 Hz, 1 H)8.49(d, J = 2.35 Hz, 1 H) 8.25 (td, J = 8.12, 2.54 Hz, 1 H) 8.02(d, J =8.61 Hz, 1 H) 7.70(d, J = 7.43 Hz, 1 H) 7.46-7.61(m, 2 H) 7.40(dd, J =8.61, 2.74 Hz, 1 H) 7.14-7.27 (m, 1 H) 6.75(d, J = 8.61 Hz, 1 H)4.37-4.49(m, 1 H) 4.23-4.37(m, 4 H). 4.5

(400 MHz, DMSO-d₆) 8.74(d, J = 2.35 Hz, 1 H) 8.68(d, J = 2.35 Hz, 1 H)8.49(d, J = 2.35 Hz, 1 H) 8.25 (td, J = 8.12, 2.54 Hz, 1 H) 8.02(d, J =8.61 Hz, 1 H) 7.70(d, J = 7.43 Hz, 1 H) 7.46-7.61(m, 2 H) 7.40(dd, J =8.61, 2.74 Hz, 1 H) 7.14-7.27 (m, 1 H) 6.75(d, J = 8.61 Hz, 1 H)4.37-4.49(m, 1 H) 4.23-4.37(m, 4 H). 4.6

(400 MHz, DMSO-d₆) 8.64(d, J = 2.35 Hz, 1 H) 8.60(d, J = 1.96 Hz, 1 H)8.02(d, J = 9.00 Hz, 1 H) 7.78 (d, J = 8.22 Hz, 1 H) 7.70(d, J = 7.82Hz, 1 H) 7.43-7.62(m, 2 H) 7.21(t, J = 7.04 Hz, 1 H) 6.76(d, J = 9.00Hz, 1 H) 6.59(d, J = 8.22 Hz, 1 H) 4.31 (br. s., 1 H) 4.23(t, J = 6.65Hz, 2 H) 4.00-4.14(m, 2 H) 3.97(s, 3 H) 3.94(s, 3 H). 4.7

(400 MHz, DMSO-d₆) 8.77(d, J = 2.3 Hz, 2 H), 8.70(d, J = 2.3 Hz, 1 H),8.69(s, 1 H), 8.07-7.97(m, 2 H), 7.70(d, J = 8.2 Hz, 1 H), 7.59- 7.47(m,2 H), 7.26-7.16(m, 1 H), 6.76(d, J = 9.0 Hz, 1 H), 4.50-4.40 (m, 1 H),4.37-4.23(m, 4 H) 4.8

(500 MHz, DMSO-d₆) 8.68-8.79 (m, 2 H) 8.43(d, J = 2.29 Hz, 1 H) 8.38(d,J = 9.28 Hz, 1 H) 8.00(dd, J = 8.59, 2.41 Hz, 1 H) 7.93(d, J = 7.90 Hz,1 H) 7.77(d, J = 3.55 Hz, 2 H) 7.49(dd, J = 8.08, 4.07 Hz, 1 H) 7.03(d,J = 8.59 Hz, 1 H) 7.05(d, J = 9.74 Hz, 1 H) 4.66(br. s., 2 H)4.45-4.64(m, 2 H) 3.96(s, 3 H). 4.9

(500 MHz, DMSO-d₆) 8.78(d, J = 2.41 Hz, 1 H) 8.71-8.76(m, 1 H) 8.39(d, J= 9.51 Hz, 1 H) 8.30(s, 1 H) 8.11(d, J = 9.51 Hz, 1 H) 7.93(d, J = 7.90Hz, 1 H) 7.78(d, J = 3.55 Hz, 2 H) 7.44-7.52(m, 1 H) 7.05(d, J = 9.28Hz, 1 H) 4.52-4.72(m, 5 H) 2.37(s, 3 H). 4.10

(500 MHz, DMSO-d₆) 8.83(s, 1 H) 8.79(d, J = 2.29 Hz, 1 H) 8.76(s, 2 H)8.39(d, J = 9.39 Hz, 1 H) 8.09(d, J = 7.90 Hz, 1 H) 7.93(d, J = 7.90 Hz,1 H) 7.77(br. s., 2 H) 7.64(dd, J = 7.73, 4.75 Hz, 1 H) 7.50(d, J = 8.02Hz, 1 H) 7.05(d, J = 9.39 Hz, 1 H) 4.67(br. s., 2 H) 4.60(br. s., 3 H).4.11

(600 MHz, DMSO-d₆) 8.80(s, 1 H), 8.77-8.71(m, 1 H) , 8.37(d, J = 9.3 Hz,1 H), 8.18-8.08(m, J = 8.1 Hz, 2 H), 7.92(d, J = 7.9 Hz, 1 H), 7.91-7.87(m, J = 8.1 Hz, 2 H), 7.78(br. s., 2 H), 7.48(t, J = 5.7 Hz, 1 H),7.02(d, J = 9.3 Hz, 1 H), 4.70-4.54 (m, 6 H) 4.12

(500 MHz, DMSO-d₆) 8.57(s, 2 H) 8.17(s, 1 H) 8.03(d, J = 9.05 Hz, 1 H)7.70(d, J = 7.90 Hz, 1 H) 7.65 (dd, J = 8.59, 2.29 Hz, 1 H) 7.57(d, J =8.36 Hz, 1 H) 7.52(t, J = 7.56 Hz, 1 H) 7.21(t, J = 7.33 Hz, 1 H) 6.76(d, J = 8.94 Hz, 1 H) 6.60(d, J = 8.59 Hz, 1 H) 6.35(s, 2 H) 4.47(q, J =7.48 Hz, 1 H), 4.37(t, J = 8.08 Hz, 2 H) 4.22-4.30(m, 2 H). 4.13

(500 MHz, DMSO-d₆) 8.67(d, J = 2.29 Hz, 1 H) 8.63(d, J = 2.29 Hz, 1 H)8.08(d, J = 2.52 Hz, 1 H) 8.02 (d, J = 8.94 Hz, 1 H) 7.89-7.96(m, 1 H)7.70(d, J = 8.02 Hz, 1 H) 7.54- 7.63(m, 1 H) 7.45-7.54(m, 1 H) 7.21(t, J= 7.33 Hz, 1 H) 7.11(d, J = 1.95 Hz, 1 H) 6.75(d, J = 8.94 Hz, 1 H)5.57(br. s., 1 H) 4.31-4.45(m, 3 H) 4.20-4.31(m, 2 H). 4.14

(500 MHz, DMSO-d₆) 8.72(d, J = 2.29 Hz, 1 H), 8.65(d, J = 2.29 Hz, 1 H)8.01(d, J = 8.94 Hz, 1 H) 7.93 (t, J = 7.85 Hz, 1 H) 7.69(d, J = 7.90Hz, 1 H) 7.63(d, J = 7.33 Hz, 1 H) 7.55(d, J = 8.48 Hz, 1 H) 7.51(t, J =7.56 Hz, 1 H) 7.20(t, J = 7.27 Hz, 1 H) 6.98(d, J = 8.25 Hz, 1 H) 6.76(d, J = 8.94 Hz, 1 H) 4.81-4.95(m, 1 H) 4.40(t, J = 8.25 Hz, 2 H) 4.21-4.33(m, 2 H) 4.00(s, 3 H). 4.15

(400 MHz, CD₃OD) 8.94(d, J = 4.69 Hz, 1 H) 8.88(d, J = 2.35 Hz, 1 H)8.72(d, J = 2.35 Hz, 1 H) 8.38(d, J = 9.39 Hz, 1 H) 8.06(d, J = 7.04 Hz,1 H) 7.94(d, J = 7.82 Hz, 1 H) 7.90 (dd, J = 7.92, 4.79 Hz, 1 H) 7.75-7.87(m, 2 H) 7.49-7.65(m, 1 H) 7.00(d, J = 9.39 Hz, 1 H) 4.62-4.84 (m, 4H) 4.14(quin, J = 7.34 Hz, 1 H). 4.16

(400 MHz, CD₃OD) 8.67-8.70(m, 1 H) 8.65-8.67(m, 1 H) 8.63(s, 2 H)8.38(d, J = 9.39 Hz, 1 H) 7.94(d, J = 7.63 Hz, 1 H) 7.75-7.88(m, 2 H)7.51-7.61(m, 1 H) 7.02(d, J = 9.59 Hz, 1 H) 4.67-4.85(m, 5 H) 3.32 (s, 6H). 4.17

(400 MHz, CD₃OD) 8.86(d, J = 2.35 Hz, 1 H) 8.76(d, J = 2.54 Hz, 1 H)8.68(d, J = 5.28 Hz, 1 H) 8.55(s, 1 H) 8.38(d, J = 9.59 Hz, 1 H) 7.94(d,J = 8.02 Hz, 1 H) 7.75-7.89(m, 2 H) 7.70(d, J = 5.48 Hz, 1 H) 7.56(td, J= 7.48, 1.27 Hz, 1 H) 7.00(d, J = 9.39 Hz, 1 H) 4.75-4.83(m, 2 H)4.63-4.75(m, 2 H) 4.19-4.37(m, 1 H) 2.34(s, 3 H). 4.18

(300 MHz, CD₃OD) 9.31(d, J = 2.19 Hz, 1 H) 9.16(d, J = 2.05 Hz, 1 H)8.85(d, J = 2.34 Hz, 1 H) 8.78(d, J = 2.34 Hz, 1 H) 8.62(t, J = 2.12 Hz,1 H) 8.38(d, J = 9.50 Hz, 1 H) 7.94 (d, J = 8.04 Hz, 1 H) 7.73-7.89(m, 2H) 7.56(td, J = 7.38, 1.46 Hz, 1 H) 7.02(d, J = 9.35 Hz, 1 H) 4.76-4.84(m, 4 H) 4.56-4.73(m, 1 H) 3.36 (s, 3 H). 4.19

(300 MHz, CD₃OD) 8.80(d, J = 2.48 Hz, 1 H) 8.73(d, J = 2.48 Hz, 1 H)8.60-8.69(m, 2 H) 8.37(d, J = 9.35 Hz, 1 H) 8.01-8.11(m, 1 H) 7.93 (d, J= 7.89 Hz, 1 H) 7.72-7.89(m, 2 H) 7.48-7.62(m, 1 H) 7.00(d, J = 9.50 Hz,1 H) 4.73-4.83(m, 4 H) 4.58-4.72(m, 1 H) 2.56(s, 3 H). 4.20

(300 MHz, CD₃OD) 8.80(d, J = 2.34 Hz, 1 H) 8.73(d, J = 2.48 Hz, 1 H)8.48(d, J = 2.78 Hz, 1 H) 8.31-8.43 (m, 2 H) 7.93(d, J = 7.89 Hz, 1 H)7.74-7.88(m, 2 H) 7.71(dd, J = 2.78, 1.75 Hz, 1 H) 7.55(ddd, J = 8.00,6.76, 1.46 Hz, 1 H) 7.00(d, J = 9.50 Hz, 1 H) 4.73-4.82(m, 4 H)4.60-4.73(m, 1 H) 4.03(s, 3 H). 4.21

(500 MHz, DMSO-d₆) 8.68(d, J = 2.41 Hz, 1H) 8.63(d, J = 2.41 Hz, 1 H)8.01(d, J = 8.82 Hz, 1 H) 7.69 (d, J = 7.67 Hz, 1 H) 7.53-7.63(m, 3 H)7.47-7.53(m, 1 H) 7.43(dd, J = 8.19, 2.00 Hz, 1 H) 7.14-7.26 (m, 1 H)6.74(d, J = 8.94 Hz, 1 H) 4.36-4.46(m, 1 H) 4.32(t, J = 7.96 Hz, 2 H)4.20-4.29(m, 2 H) 2.45 (s, 3 H). 4.22

(500 MHz, DMSO-d₆) 8.68(d, J = 2.41 Hz, 1 H) 8.63(d, J = 2.41 Hz, 1 H)8.04(d, J = 8.82 Hz, 1 H) 7.71 (d, J = 7.68 Hz, 1 H) 7.50-7.62(m, 2 H)7.48(t, J = 7.85 Hz, 1 H) 7.39(d, J = 10.65 Hz, 1 H) 7.33(dd, J = 7.73,1.55 Hz, 1 H) 7.22(t, J = 7.39 Hz, 1 H) 6.76(d, J = 9.05 Hz, 1 H) 4.39-4.51(m, 1 H) 4.21-4.39(m, 4 H) 2.35(s, 3 H). 4.23

(500 MHz, DMSO-d₆) 8.62(d, J = 2.41 Hz, 1 H) 8.59(d, J = 2.29 Hz, 1 H)8.01(d, J = 8.82 Hz, 1 H) 7.70 (d, J = 7.22 Hz, 1 H) 7.59(d, J = 2.06Hz, 1 H) 7.54-7.58(m, 1 H) 7.47- 7.54(m, 1 H) 7.39(dd, J = 8.42, 2.12Hz, 1 H) 7.17-7.25(m, 1 H) 7.14 (d, J = 8.36 Hz, 1 H) 6.75(d, J = 8.82Hz, 1 H) 4.40-4.51(m, 1 H) 4.33(t, J = 8.13 Hz, 2 H) 4.19-4.29(m, 2 H).4.24

(500 MHz, DMSO-d₆) 8.73(d, J = 2.41 Hz, 1 H) 8.66(d, J = 2.41 Hz, 1 H)8.02(d, J = 8.94 Hz, 1 H) 7.70 (d, J = 7.79 Hz, 1 H) 7.54-7.60(m, 1 H)7.46-7.54(m, 2 H) 7.43(d, J = 9.39 Hz, 2 H) 7.14-7.28(m, 1 H) 6.75(d, J= 8.82 Hz, 1 H) 4.36-4.47 (m, 1 H) 4.24-4.36(m, 4 H) 3.94 (s, 3 H). 4.25

(500 MHz, DMSO-d₆) 8.64(d, J = 2.41 Hz, 1 H) 8.60(d, J = 2.41 Hz, 1 H)8.01(d, J = 8.82 Hz, 1 H) 7.69 (d, J = 7.33 Hz, 1 H) 7.53-7.58(m, 1 H)7.45-7.53(m, 2 H) 7.37(dd, J = 8.53, 1.78 Hz, 1 H) 7.31(t, J = 8.53 Hz,1 H) 7.15-7.25(m, 1 H) 6.74 (d, J = 8.94 Hz, 1 H) 4.41-4.55(m, 1 H)4.32(t, J = 8.13 Hz, 2 H) 4.13- 4.28(m, 4 H) 1.41(t, J = 6.99 Hz, 3 H).4.26

(500 MHz, DMSO-d₆) 8.65(d, J = 2.41 Hz, 1 H) 8.61(d, J = 2.41 Hz, 1 H)8.02(d, J = 8.93 Hz, 1 H) 7.70 (d, J = 7.56 Hz, 1 H) 7.68(d, J = 2.18Hz, 1 H) 7.44-7.62(m, 3 H) 7.30 (d, J = 8.59 Hz, 1 H) 7.14-7.25(m, 1 H)6.75(d, J = 8.94 Hz, 1 H) 4.39- 4.56(m, 1 H) 4.32(t, J = 8.13 Hz, 2 H)4.06-4.29(m, 4 H) 1.42(t, J = 6.93 Hz, 3 H). 4.27

(500 MHz, DMSO-d₆) 8.65(d, J = 2.41 Hz, 1 H) 8.61(d, J = 2.41 Hz, 1 H)8.02(d, J = 8.94 Hz, 1 H) 7.70 (d, J = 7.45 Hz, 1 H) 7.67(d, J = 2.18Hz, 1 H) 7.46-7.61(m, 3 H) 7.30 (d, J = 8.59 Hz, 1 H) 7.16-7.25(m, 1 H)6.75(d, J = 8.82 Hz, 1 H) 4.40- 4.52(m, 1 H) 4.32(t, J = 8.13 Hz, 2 H)4.21-4.29(m, 2 H) 4.13(t, J = 6.42 Hz, 2 H) 1.82(sxt, J = 6.99 Hz, 2 H)1.05(t, J = 7.39 Hz, 3 H). 4.28

(500 MHz, DMSO-d₆) 8.76(d, J = 2.41 Hz, 1 H) 8.68(d, J = 2.29 Hz, 1 H)8.02(d, J = 8.82 Hz, 1 H) 7.88 (d, J = 8.59 Hz, 1 H) 7.77-7.85(m, 2 H)7.70(d, J = 7.90 Hz, 1 H) 7.54- 7.61(m, 1 H) 7.44-7.54(m, 1 H)7.12-7.29(m, 1 H) 6.75(d, J = 8.82 Hz, 1 H) 4.42(quin, J = 7.25 Hz, 1 H)4.30(d, J = 7.22 Hz, 4 H). 4.29

(500 MHz, DMSO-d₆) 8.59-8.63 (m, 1 H) 8.54-8.59(m, 1 H) 8.01 (d, J =8.93 Hz, 1 H) 7.69(d, J = 7.68 Hz, 1 H) 7.53-7.59(m, 1 H) 7.47- 7.53(m,1 H) 7.33-7.46(m, 2 H) 7.14-7.28(m, 1 H) 7.10(d, J = 8.36 Hz, 1 H)6.74(d, J = 8.94 Hz, 1 H) 4.39-4.52(m, 1 H) 4.33(t, J = 8.13 Hz, 2H)4.18-4.29(m, 2 H) 3.88 (s, 3 H) 2.26(s, 3 H). 4.30

(500 MHz, DMSO-d₆) 8.70(d, J = 2.41 Hz, 1 H) 8.63(d, J = 2.41 Hz, 1 H)8.02(d, J = 8.93 Hz, 1 H) 7.70 (d, J = 7.67 Hz, 1 H) 7.48-7.60(m, 2 H)7.10-7.31(m, 1 H) 6.85-7.06 (m, 3 H) 6.75(d, J = 8.82 Hz, 1 H) 4.75(dt,J = 12.03, 6.01 Hz, 1 H) 4.36- 4.50(m, 1 H) 4.18-4.35(m, 4 H) 1.32(d, J= 5.97 Hz, 6 H). 4.31

(500 MHz, DMSO-d₆) 8.69(d, J = 2.41 Hz, 1 H) 8.63(d, J = 2.41 Hz, 1 H)8.02(d, J = 8.94 Hz, 1 H) 7.70 (d, J = 7.56 Hz, 1 H) 7.54-7.58(m, 1 H)7.48-7.54(m, 1 H) 7.14-7.31 (m, 4 H) 6.75(d, J = 8.82 Hz, 1 H)4.37-4.50(m, 1 H) 4.20-4.36(m, 4 H) 2.44(s, 3 H). 4.32

(500 MHz, DMSO-d₆) 8.71(d, J = 2.41 Hz, 1 H) 8.64(d, J = 2.41 Hz, 1 H)8.02(d, J = 8.93 Hz, 1 H) 7.80- 7.87(m, 1 H) 7.70(d, J = 7.67 Hz, 1 H)7.54-7.65(m, 3 H) 7.48-7.54 (m, 1 H) 7.17-7.24(m, 1 H) 6.75 (d, J = 8.94Hz, 1 H) 4.37-4.47(m, 1 H) 4.22-4.36(m, 4 H). 4.33

(500 MHz, DMSO-d₆) 8.70(d, J = 2.41 Hz, 1 H) 8.64(d, J = 2.41 Hz, 1 H)8.01(d, J = 8.82 Hz, 1 H) 7.66- 7.74(m, 2 H) 7.58-7.66(m, 1 H)7.53-7.58(m, 1 H) 7.48-7.53(m, 1 H) 7.41-7.48(m, 1 H) 7.12-7.26 (m, 1 H)6.74(d, J = 8.94 Hz, 1 H) 4.38-4.48(m, 1 H) 4.31(t, J = 8.08 Hz, 2 H)4.21-4.29(m, 2 H). 4.34

(500 MHz, DMSO-d₆) 8.72(d, J = 2.41 Hz, 1 H) 8.65(d, J = 2.41 Hz, 1 H)8.02(d, J = 8.93 Hz, 1 H) 7.87 (d, J = 1.95 Hz, 1 H) 7.82(d, J = 8.25Hz, 1 H) 7.70(d, J = 7.45 Hz, 1 H) 7.60(dd, J = 8.31, 2.00 Hz, 1 H)7.54- 7.58(m, 1 H) 7.48-7.54(m, 1 H) 7.16-7.27(m, 1 H) 6.76(d, J = 8.82Hz, 1 H) 4.37-4.47(m, 1 H) 4.32(t, J = 8.02 Hz, 2 H) 4.24-4.30(m, 2 H).4.35

(500 MHz, DMSO-d₆) 8.63(d, J = 2.41 Hz, 1 H) 8.60(d, J = 2.41 Hz, 1 H)8.02(d, J = 8.82 Hz, 1 H) 7.70 (d, J = 7.56 Hz, 1 H) 7.53-7.58(m, 1 H)7.48-7.53(m, 1 H) 7.36(s, 1 H) 7.26-7.34(m, 2 H) 7.17-7.24(m, 1 H)6.75(d, J = 8.94 Hz, 1 H) 4.36- 4.47(m, 1 H) 4.32(t, J = 8.02 Hz, 2 H)4.21-4.29(m, 2 H) 2.34(s, 3 H) 2.33(s, 3 H). 4.36

(500 MHz, DMSO-d₆) 8.68(d, J = 2.29 Hz, 1 H) 8.63(d, J = 2.41 Hz, 1 H)8.01(d, J = 8.82 Hz, 1 H) 7.69 (d, J = 7.56 Hz, 1 H) 7.64(d, J = 1.49Hz, 1 H) 7.48-7.59(m, 3 H) 7.46 (dd, J = 7.79, 1.60 Hz, 1 H) 7.13-7.28(m, 1 H) 6.75(d, J = 8.82 Hz, 1 H) 4.37-4.48(m, 1 H) 4.19-4.36 (m, 4H) 2.44(s, 3 H). 4.37

(500 MHz, DMSO-d₆) 8.70(d, J = 2.41 Hz, 1 H) 8.63(d, J = 2.41 Hz, 1 H)8.02(d, J = 8.82 Hz, 1 H) 7.70 (d, J = 7.67 Hz, 1 H) 7.54-7.59(m, 1 H)7.49-7.54(m, 1 H) 7.45(s, 2 H) 7.35(s, 1 H) 7.12-7.27(m, 1 H) 6.76(d, J= 8.82 Hz, 1 H) 4.36-4.47 (m, 1 H) 4.20-4.36(m, 4 H) 2.44 (s, 3 H). 4.38

(500 MHz, DMSO-d₆) 8.66(d, J = 2.41 Hz, 1 H) 8.61(d, J = 2.41 Hz, 1 H)8.01(d, J = 8.94 Hz, 1 H) 7.70 (d, J = 7.56 Hz, 1 H) 7.54-7.58(m, 1 H)7.48-7.54(m, 2 H) 7.41-7.47 (m, 1 H) 7.31(t, J = 9.11 Hz, 1 H)7.17-7.25(m, 1 H) 6.74(d, J = 8.82 Hz, 1 H) 4.37-4.45(m, 1 H) 4.32(t, J= 8.02 Hz, 2 H) 4.21-4.29(m, 2 H) 2.26-2.42(m, 3 H). 4.39

(500 MHz, DMSO-d₆) 9.36(s, 1 H) 9.08(s, 2 H) 8.78(d, J = 2.41 Hz, 1 H)8.73(d, J = 2.29 Hz, 1 H) 8.03(d, J = 8.82 Hz, 1 H) 7.71(d, J = 8.02 Hz,1 H) 7.48-7.60(m, 2 H) 7.22(t, J = 7.33 Hz, 1 H) 6.76(d, J = 8.82 Hz, 1H) 4.41-4.52(m, 1 H) 4.23-4.39 (m, 4 H). 4.40

(500 MHz, DMSO-d₆) 8.74(d, J = 2.41 Hz, 1 H) 8.67(d, J = 2.41 Hz, 1 H)8.06(s, 1 H) 8.02(d, J = 8.94 Hz, 1 H) 7.93(s, 2 H) 7.70(d, J = 7.67 Hz,1 H) 7.54-7.60(m, 1 H) 7.48-7.54(m, 1 H) 7.16-7.27(m, 1 H) 6.76(d, J =8.94 Hz, 1 H) 4.36- 4.45(m, 1 H) 4.26-4.36(m, 4 H). 4.41

(300 MHz, MeOH) 8.57(1 H, d, J = 2.5 Hz), 8.48(1 H, d, J = 2.3 Hz),8.03(1 H, d, J = 9.1 Hz), 7.70(2 H, m), 7.54(1 H, m), 7.23-7.30(1 H, m),6.78(1 H, d, J = 8.9 Hz), 5.99(1 H, br. s.), 4.38-4.66(3 H, m), 4.02 (4H, m), 3.32-3.37(2 H, m), 2.61 (2H, m) 4.42

(300 MHz, MeOH) 8.57(1 H, d, J = 2.3 Hz), 8.48(1 H, d, J = 2.5 Hz),8.04(1 H, d, J = 8.9 Hz), 7.71(2 H, d, J = 7.7 Hz), 7.58(1 H, t, J = 7.7Hz), 7.22-7.34(1 H, m), 6.79(1 H, d, J = 8.9 Hz), 5.99(1 H, s),4.50-4.70 (3 H, m), 4.39-4.50(3 H, m), 2.46- 2.48(2 H, m), 1.45(1 H, s),1.39(6 H, s) 4.43

(300 MHz, DMSO-d₆) 13.31(1 H, br. s.), 8.50(1 H, d, J = 2.2 Hz), 8.54 (1H, d, J = 2.3 Hz), 8.29(1 H, s), 7.97-8.08(2 H, m), 7.71(1 H, d, J =7.9Hz), 7.47-7.61(2 H, m), 7.22 (1 H, t, J = 6.7 Hz), 6.79(1 H, d, J = 8.9Hz), 4.42-4.71(3 H, m), 4.21- 4.42(2 H, m) 4.44

(500 MHz, DMSO-d₆) 8.76(d, J = 2.41 Hz, 1 H) 8.68(d, J = 2.29 Hz, 1 H)8.02(d, J = 8.82 Hz, 1 H) 7.88 (d, J = 8.59 Hz, 1 H) 7.77-7.85(m, 2 H)7.70(d, J = 7.90 Hz, 1 H) 7.54- 7.61(m, 1 H) 7.44-7.54(m ,1 H)7.12-7.29(m, 1H) 6.75(d, J = 8.82 Hz, 1 H) 4.42(quin, J = 7.25 Hz, 1 H)4.30(d, J = 7.22 Hz, 4 H). 4.45

(500 MHz, DMSO-d₆) 8.72(d, J = 2.29 Hz, 1 H) 8.65(d, J = 2.29 Hz, 1 H)8.01(d, J = 8.94 Hz, 1 H) 7.93 (t, J = 7.85 Hz, 1 H) 7.69(d, J = 7.90Hz, 1 H) 7.63(d, J = 7.33 Hz, 1 H) 7.55(d, J = 8.48 Hz, 1 H) 7.51(t, J =7.56 Hz, 1 H) 7.20(t, J = 7.27 Hz, 1 H) 6.98(d, J = 8.25 Hz, 1 H) 6.76(d, J = 8.94 Hz, 1 H) 4.81-4.95(m, 1 H) 4.40(t, J = 8.25 Hz, 2 H) 4.21-4.33(m, 2 H) 4.00(s, 3 H).

Example 5.1 2-(3-(3-PHENYLPYRAZIN-2-YL)AZETIDIN-1-YL)QUINOLINE

A glass microwave reaction vessel was charged with2-(3-(3-chloropyrazin-2-yl)azetidin-1-yl)quinoline (0.085 g, 0.286mmol), phenylboronic acid (0.070 g, 0.573 mmol, Aldrich), potassiumphosphate (0.152 g, 0.716 mmol, Alfa Aesar),bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium (II)(0.020 g, 0.029 mmol, Aldrich), water (0.400 mL) and dioxane (1.6 mL).The mixture was purged with Argon gas and heated in an Initiatormicrowave reactor (Personal Chemistry, Biotage AB, Inc., Upssala,Sweden) at 100° C. for 30 min. LCMS showed the product. The mixture wasdiluted with EtOAc and washed with Na₂CO₃ and brine. The organic layerwas dried over Na₂SO₄ and concentrated in vacuo. The crude was purifiedby silica gel chromatography (12 g, 10%-100% EtOAc-Hexane). The productwas obtained as a white solid (85 mg, 88%).

The following Table 17A lists compounds of Examples 5.1 to 5.43, whichwere made analogous to Scheme 5 by using the appropriate materials andreaction conditions, which are listed in Table 17B. The NMR data of theExamples are listed in Table 17C.

TABLE 17A EXAMPLES 5.1 TO 5.43 ESI-MS Ex. # Structure Chemical Name(M + 1) IC₅₀ (μM) 5.1

2-(3-(3-phenylpyrazin-2- yl)azetidin-1-yl)quinoline 339 0.0012 5.2

2-(3-(3-(4- methoxyphenyl)pyrazin-2- yl)azetidin-1-yl)quinoline 3690.002 5.3

2-(3-(3-(4- fluorophenyl)pyrazin-2- yl)azetidin-1-yl)quinoline 357 0.0025.4

2-(3-(3-(2- fluorophenyl)pyrazin-2- yl)azetidin-1-yl)quinoline 357 0.015.5

2-(3-(3-(3- fluorophenyl)pyrazin-2- yl)azetidin-1-yl)quinoline 357 0.0045.6

2-(3-(3-(pyridin-4- yl)pyrazin-2-yl)azetidin-1- yl)quinoline 340 0.0045.7

3-(3-(1-(quinolin-2- yl)azetidin-3-yl)pyrazin-2- yl)benzonitrile 3640.003 5.8

4-(3-(1-(quinolin-2- yl)azetidin-3-yl)pyrazin-2- yl)benzonitrile 3640.003 5.9

methyl 3-(3-(1-(quinolin- 2-yl)azetidin-3-yl)pyrazin- 2-yl)benzoate 3970.0002 5.10

ethyl 4-(3-(1-(quinolin-2- yl)azetidin-3-yl)pyrazin-2- yl)benzoate 4110.002 5.11

2-(3-(3-(2- methoxypyridin-4- yl)pyrazin-2-yl)azetidin-1- yl)quinoline370 0.002 5.12

2-(3-(3-(2-fluoropyridin- 4-yl)pyrazin-2-yl)azetidin- 1-yl)quinoline 3580.01 5.13

2-(3-(3-(3- (methylthio)phenyl)pyrazin- 2-yl)azetidin-1- yl)quinoline385 0.004 5.14

1-(4-(3-(1-(quinolin-2- yl)azetidin-3-yl)pyrazin-2- yl)phenyl)ethanone381 0.003 5.15

2-(3-(3-(4- phenoxyphenyl)pyrazin-2- yl)azetidin-1-yl)quinoline 4310.034 5.16

2-(3-(3-(4- (trifluoromethyl)phenyl)py- razin-2-yl)azetidin-1-yl)quinoline 407 0.027 5.17

2-(3-(3-(3-fluoro-4- methoxyphenyl)pyrazin-2- yl)azetidin-1-yl)quinoline387 0.003 5.18

N,N-dimethyl-3-(3-(1- (quinolin-2-yl)azetidin-3- yl)pyrazin-2-yl)aniline382 0.002 5.19

N-methyl-3-(3-(1- (quinolin-2-yl)azetidin-3- yl)pyrazin-2-yl)benzamide396 0.0007 5.20

tert-butyl 4-(3-(1- (quinolin-2-yl)azetidin-3- yl)pyrazin-2-yl)-5,6-dihydropyridine-1(2H)- carboxylate 444 0.0007 5.21

2-(3-(3-([1,1′-biphenyl]-3- yl)pyrazin-2-yl)azetidin-1- yl)quinoline 4150.002 5.22

2-fluoro-4-(3-(1- (quinolin-2-yl)azetidin-3- yl)pyrazin-2-yl)benzonitrile 382 0.006 5.23

2-fluoro-5-(3-(1- (quinolin-2-yl)azetidin-3- yl)pyrazin-2-yl)benzonitrile 382 0.007 5.24

N,N-dimethyl-3-(3-(1- (quinolin-2-yl)azetidin-3-yl)pyrazin-2-yl)benzamide 410 0.018 5.25

2-(3-(3-(2- methoxyphenyl)pyrazin-2- yl)azetidin-1-yl)quinoline 3690.002 5.26

2-(3-(3-(3- (trifluoromethyl)phenyl)py- razin-2-yl)azetidin-1-yl)quinoline 407 0.01344 5.27

2-(3-(3-(3- ethoxyphenyl)pyrazin-2- yl)azetidin-1-yl)quinoline 3830.00388 5.28

1-(3-(3-(1-(quinolin-2- yl)azetidin-3-yl)pyrazin-2- yl)phenyl)ethanone381 0.00124 5.29

(3-(3-(1-(quinolin-2- yl)azetidin-3-yl)pyrazin-2- yl)phenyl)methanol 3690.00676 5.30

2-(3-(3-(3- (trifluoromethoxy)phenyl) pyrazin-2-yl)azetidin-1-yl)quinoline 423 0.00665 5.31

2-(3-(3-(3- (benzyloxy)phenyl)pyrazin- 2-yl)azetidin-1- yl)quinoline 4450.01077 5.32

N-cyclopropyl-3-(3-(1- (quinolin-2-yl)azetidin-3-yl)pyrazin-2-yl)benzamide 422 0.00337 5.33

N,N-dimethyl-3-(3-(1- (quinolin-2-yl)azetidin-3- yl)pyrazin-2-yl)benzenesulfonamide 446 0.01703 5.34

2-(3-(3-(4- ethoxyphenyl)pyrazin-2- yl)azetidin-1-yl)quinoline 3830.01717 5.35

(4-(3-(1-(quinolin-2- yl)azetidin-3-yl)pyrazin-2- yl)phenyl)methanol 3690.00519 5.36

2-(3-(3-(4- propylphenyl)pyrazin-2- yl)azetidin-1-yl)quinoline 3810.00995 5.37

2-(3-(3-(4- ethylphenyl)pyrazin-2- yl)azetidin-1-yl)quinoline 3670.00609 5.38

N,N-dimethyl-4-(3-(1- (quinolin-2-yl)azetidin-3- yl)pyrazin-2-yl)aniline382 0.01217 5.39

2-(3-(3-(4- (trifluoromethoxy)phenyl) pyrazin-2-yl)azetidin-1-yl)quinoline 423 0.01747 5.40

2-(3-(3-(4- isopropoxyphenyl)pyrazin- 2-yl)azetidin-1- yl)quinoline 3970.00723 5.41

2-methyl-2-(4-(3-(1- (quinolin-2-yl)azetidin-3- yl)pyrazin-2-yl)phenyl)propanenitrile 406 0.00737 5.42

4-((4-(3-(1-(quinolin-2- yl)azetidin-3-yl)pyrazin-2-yl)phenyl)sulfonyl)morpho- line 488 0.03337 5.43

2-(3-(3-(4-(piperidin-1- ylsulfonyl)phenyl)pyrazin- 2-yl)azetidin-1-yl)quinoline 486 0.02119

TABLE 17B STARTING MATERIALS AND REACTION CONDITION FOR PREPARATION OFEXAMPLES 5.1 TO 5.43. Unless otherwise stated, all starting materialsare commercially available from common vendors. Reaction Purification EX# Key Starting Material(s) Key Starting Material(s) Condition Method*5.1

Dioxane/water, 100° C., μW A 5.2

Dioxane/water, 100° C., μW A 5.3

Dioxane/water, 100° C., μW A 5.4

Dioxane/water, 100° C., μW A 5.5

Dioxane/water, 100° C., μW A 5.6

Dioxane/water, 100° C., μW B 5.7

Dioxane/water, 100° C., μW A 5.8

Dioxane/water, 100° C., μW A 5.9

Dioxane/water, 100° C., μW A 5.10

Dioxane/water, 100° C., μW A 5.11

Dioxane/water, 100° C., μW C 5.12

Dioxane/water, 100° C., μW C 5.13

Dioxane/water, 100° C., μW A 5.14

Dioxane/water, 100° C., μW A 5.15

Dioxane/water, 100° C., μW A 5.16

Dioxane/water, 100° C. A 5.17

Dioxane/water, 100° C. A 5.18

Dioxane/water, 100° C. A 5.19

Dioxane/water, 100° C. A 5.20

Dioxane/water, 100° C. A 5.21

Dioxane/water, 100° C. A 5.22

Dioxane/water, 100° C. A 5.23

Dioxane/water, 100° C. A 5.24

Dioxane/water, 100° C. C 5.25

Dioxane/water, 100° C. A 5.26

Dioxane/water, 100° C. D 5.27

Dioxane/water, 100° C. D 5.28

Dioxane/water, 100° C. D 5.29

Dioxane/water, 100° C. D 5.30

Dioxane/water, 100° C. D 5.31

Dioxane/water, 100° C. D 5.32

Dioxane/water, 100° C. D 5.33

Dioxane/water, 100° C. D 5.34

Dioxane/water, 100° C. D 5.35

Dioxane/water, 100° C. D 5.36

Dioxane/water, 100° C. D 5.37

Dioxane/water, 100° C. D 5.38

Dioxane/water, 100° C. D 5.39

Dioxane/water, 100° C. D 5.40

Dioxane/water, 100° C. D 5.41

Dioxane/water, 100° C. D 5.42

Dioxane/water, 100° C. D 5.43

Dioxane/water, 100° C. D *PURIFICATION CONDITIONS: METHOD A-purification by silica gel chromatography: (ISCO 12 g RediSep-silicacolumn, eluting with a gradient of 10% to 100% EtOAc in hexane). METHODB- purification by silica gel chromatography: (ISCO 12 g RediSep-silicacolumn, eluting with a gradient of 0% to 10% MeOH in CH₂Cl₂). METHOD C-reverse-phase HPLC (Shimazu; Gemini 10 μM C18 110A AXIA, 100 × 50 mmcolumn) eluting with 0.1% TFA- H₂O:0.1% TFA CH₃CN (10% → 55%). Thefractions containing the desired product were combined, neutralized withNa₂CO₃, and extracted with a mixed solvent of CHCl₃:i-PrOH(3:1) threetimes. The organic phse was dried over Na₂SO₄ and concentrated in vacuo.METHOD D- reverse phse purification using the following conditions:(Instrumentation: MS - Waters SQ; UV - Waters 2487 or Waters PD;Solvents: A: Water w/ 0.1% NH₄OH B: Acetonitrile w/ 0.1% NH₄OH; Column:Phenomenex Gemini-NX C18 100A 5 um 21 × 100; Flow Rate: 44 mL/min. 10min Method, variable gradient over 8 min).

TABLE 17C 1H NMR δ (PPM) DATA FOR EXAMPLES 5.1 TO 5.43 Ex. # StructureNMR 5.1

(400 MHz, CHLOROFORM-d) 4.32-4.53 (m, 5 H) 6.61 (d, J = 9.00 Hz, 1 H)7.18-7.23 (m, 1 H) 7.46- 7.55 (m, 6 H) 7.59 (d, J = 8.02 Hz, 1 H) 7.72(d, J = 8.41 Hz, 1 H) 7.85 (d, J = 9.00 Hz, 1 H) 8.55 (dd, J = 15.16,2.45 Hz, 2 H). 5.2

(400 MHz, CHLOROFORM-d) 3.90 (s, 3 H) 4.38- 4.52 (m, 5 H) 6.62 (d, J =8.80 Hz, 1 H) 7.04 (d, J = 8.61 Hz, 2 H) 7.21 (t, J = 7.43 Hz, 1 H)7.44-7.55 (m, 3 H) 7.60 (d, J = 7.83 Hz, 1 H) 7.72 (d, J = 8.41 Hz, 1 H)7.86 (d, J = 8.80 Hz, 1 H) 8.49-8.55 (m, 2 H). 5.3

(400 MHz, CHLOROFORM-d) 4.30-4.53 (m, 5 H) 6.63 (d, J = 8.80 Hz, 1 H)7.18-7.25 (m, 3 H) 7.49- 7.56 (m, 3 H) 7.60 (d, J = 8.02 Hz, 1 H) 7.72(d, J = 8.41 Hz, 1 H) 7.87 (d, J = 8.80 Hz, 1 H) 8.47-8.63 (m, 2 H). 5.4

(400 MHz, CHLOROFORM-d) 4.12-4.25 (m, 1 H) 4.34-4.49 (m, 4 H) 6.62 (d, J= 8.80 Hz, 1 H) 7.16- 7.25 (m, 2 H) 7.30-7.38 (m, 1 H) 7.45-7.56 (m, 3H) 7.59 (d, J = 8.02 Hz, 1 H) 7.72 (d, J = 8.41 Hz, 1 H) 7.86 (d, J =8.80 Hz, 1 H) 8.57 (d, J = 2.54 Hz, 1 H) 8.64 (d, J = 2.54 Hz, 1 H). 5.5

(400 MHz, CHLOROFORM-d) 4.32-4.54 (m, 5 H) 6.63 (d, J = 9.00 Hz, 1 H)7.16-7.33 (m, 4 H) 7.45-7.57 (m, 2 H) 7.60 (d, J = 7.82 Hz, 1 H) 7.72(d, J = 8.41 Hz, 1 H) 7.87 (d, J = 9.00 Hz, 1 H) 8.54 (d, J = 2.35 Hz, 1H) 8.61 (d, J = 2.35 Hz, 1 H). 5.6

(400 MHz, CHLOROFORM-d) 4.30-4.39 (m, 1 H) 4.41-4.52 (m, 4 H) 6.63 (d, J= 8.80 Hz, 1 H) 7.23 (t, J = 7.53 Hz, 1 H) 7.44-7.49 (m, 2 H) 7.51-7.57(m, 1 H) 7.61 (d, J = 7.82 Hz, 1 H) 7.73 (d, J = 8.41 Hz, 1 H) 7.88 (d,J = 8.80 Hz, 1 H) 8.58 (d, J = 2.35 Hz, 1 H) 8.66 (d, J = 2.35 Hz, 1 H)8.78-8.83 (m, 2 H). 5.7

(400 MHz, CHLOROFORM-d) 4.28-4.38 (m, 1 H) 4.40-4.51 (m, 4 H) 6.64 (d, J= 8.80 Hz, 1 H) 7.20- 7.25 (m, 1 H) 7.50-7.57 (m, 1 H) 7.59-7.84 (m, 5H) 7.85-7.92 (m, 2 H) 8.57 (d, J = 2.35 Hz, 1 H) 8.65 (d, J = 2.35 Hz, 1H). 5.8

(400 MHz, CHLOROFORM-d) 4.28-4.37 (m, 1 H) 4.39-4.50 (m, 4 H) 6.63 (d, J= 8.80 Hz, 1 H) 7.19-7.25 (m, 1 H) 7.50-7.57 (m, 1 H) 7.61 (d, J = 7.82Hz, 1 H) 7.66 (d, J = 8.41 Hz, 2 H) 7.72 (d, J = 8.41 Hz, 1 H) 7.84 (d,J = 8.41 Hz, 2 H) 7.89 (d, J = 8.80 Hz, 1 H) 8.57 (d, J = 2.54 Hz, 1 H)8.65 (d, J = 2.35 Hz, 1 H). 5.9

(400 MHz, CHLOROFORM-d) 3.97 (s, 3 H) 4.34- 4.60 (m, 5 H) 6.63 (d, J =8.80 Hz, 1 H) 7.18-7.25 (m, 1 H) 7.49-7.57 (m, 1 H) 7.58-7.68 (m, 2 H)7.69-7.80 (m, 2 H) 7.87 (d, J = 9.00 Hz, 1 H) 8.17- 8.24 (m, 2 H)8.54-8.58 (m, 1 H) 8.61 (d, J = 2.35 Hz, 1 H). 5.10

¹H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.45 (t, J = 7.14 Hz, 3 H)4.27-4.55 (m, 7 H) 6.62 (d, J = 8.80 Hz, 1 H) 7.17-7.24 (m, 1 H)7.49-7.64 (m, 4 H) 7.72 (d, J = 8.22 Hz, 1 H) 7.87 (d, J = 9.00 Hz, 1 H)8.21 (d, J = 8.41 Hz, 2 H) 8.56 (d, J = 2.35 Hz, 1 H) 8.62 (d, J = 2.35Hz, 1 H). 5.11

(400 MHz, CHLOROFORM-d) 4.02 (s, 3 H) 4.29- 4.53 (m, 5 H) 6.63 (d, J =9.00 Hz, 1 H) 6.87 (s, 1 H) 7.03 (dd, J = 5.28, 1.37 Hz, 1 H) 7.19-7.25(m, 1 H) 7.50-7.56 (m, 1 H) 7.61 (d, J = 8.02 Hz, 1 H) 7.73 (d, J = 8.41Hz, 1 H) 7.88 (d, J = 8.80 Hz, 1 H) 8.33 (d, J = 5.28 Hz, 1 H) 8.56 (d,J = 2.35 Hz, 1 H) 8.64 (d, J = 2.35 Hz, 1 H). 5.12

(400 MHz, CHLOROFORM-d) 4.28-4.39 (m, 1 H) 4.41-4.53 (m, 4 H) 6.64 (d, J= 8.80 Hz, 1 H) 7.14 (s, 1 H) 7.20-7.26 (m, 1 H) 7.35 (d, J = 5.09 Hz, 1H) 7.51-7.57 (m, 1 H) 7.61 (d, J = 7.82 Hz, 1 H) 7.73 (d, J = 8.41 Hz, 1H) 7.90 (d, J = 8.80 Hz, 1 H) 8.41 (d, J = 5.28 Hz, 1 H) 8.59 (d, J =2.35 Hz, 1 H) 8.69 (d, J = 2.35 Hz, 1 H). 5.13

(400 MHz, CHLOROFORM-d) 2.55 (s, 3 H) 4.34- 4.52 (m, 5 H) 6.63 (d, J =8.80 Hz, 1 H) 7.18-7.25 (m, 2 H) 7.35-7.47 (m, 3 H) 7.50-7.56 (m, 1 H)7.60 (d, J = 7.82 Hz, 1 H) 7.72 (d, J = 8.41 Hz, 1 H) 7.87 (d, J = 9.00Hz, 1 H) 8.54 (d, J = 2.35 Hz, 1 H) 8.59 (d, J = 2.35 Hz, 1 H). 5.14

(400 MHz, CHLOROFORM-d) 2.69 (s, 3 H) 4.30- 4.54 (m, 5 H) 6.62 (d, J =8.80 Hz, 1 H) 7.22 (t, J = 7.43 Hz, 1 H) 7.50-7.56 (m, 1 H) 7.60 (d, J =8.02 Hz, 1 H) 7.64 (d, J = 8.41 Hz, 2 H) 7.72 (d, J = 8.41 Hz, 1 H) 7.87(d, J = 8.80 Hz, 1 H) 8.12 (d, J = 8.41 Hz, 2 H) 8.57 (d, J = 2.35 Hz, 1H) 8.62 (d, J = 2.35 Hz, 1 H). 5.15

(400 MHz, CHLOROFORM-d) 4.38-4.54 (m, 5 H) 6.63 (d, J = 8.80 Hz, 1 H)7.08-7.24 (m, 6 H) 7.36- 7.44 (m, 2 H) 7.46-7.56 (m, 3 H) 7.60 (d, J =8.02 Hz, 1 H) 7.72 (d, J = 8.41 Hz, 1 H) 7.87 (d, J = 8.80 Hz, 1 H) 8.52(d, J = 2.35 Hz, 1 H) 8.56 (d, J = 2.35 Hz, 1 H). 5.16

(400 MHz, CHLOROFORM-d) 4.28-4.56 (m, 5 H) 6.63 (d, J = 9.00 Hz, 1 H)7.19-7.25 (m, 1 H) 7.54 (t, J = 7.63 Hz, 1 H) 7.61 (d, J = 8.02 Hz, 1 H)7.66 (d, J = 8.02 Hz, 2 H) 7.73 (d, J = 8.41 Hz, 1 H) 7.80 (d, J = 8.22Hz, 2 H) 7.88 (d, J = 8.80 Hz, 1 H) 8.57 (d, J = 2.35 Hz, 1 H) 8.64 (d,J = 2.35 Hz, 1 H). 5.17

(400 MHz, CHLOROFORM-d) 3.99 (s, 3 H) 4.38- 4.51 (m, 5 H) 6.63 (d, J =8.80 Hz, 1 H) 7.05-7.14 (m, 1 H) 7.18-7.25 (m, 2 H) 7.33 (dd, J = 11.74,1.96 Hz, 1 H) 7.53 (t, J = 7.63 Hz, 1 H) 7.60 (d, J = 8.02 Hz, 1 H) 7.72(d, J = 8.41 Hz, 1 H) 7.88 (d, J = 8.80 Hz, 1 H) 8.52 (d, J = 2.15 Hz, 1H) 8.56 (d, J = 2.35 Hz, 1 H). 5.18

(400 MHz, CHLOROFORM-d) 3.03 (s, 6 H) 4.34- 4.55 (m, 5 H) 6.63 (d, J =8.80 Hz, 1 H) 6.76-6.88 (m, 3 H) 7.18-7.24 (m, 1 H) 7.36 (t, J = 7.92Hz, 1 H) 7.49-7.56 (m, 1 H) 7.60 (d, J = 7.82 Hz, 1 H) 7.72 (d, J = 8.41Hz, 1 H) 7.86 (d, J = 9.00 Hz, 1 H) 8.52 (d, J = 2.35 Hz, 1 H) 8.56 (d,J = 2.35 Hz, 1 H). 5.19

(400 MHz, CHLOROFORM-d) 3.06 (d, J = 4.89 Hz, 3 H) 4.32-4.53 (m, 5 H)6.27 (br. s., 1 H) 6.62 (d, J = 9.00 Hz, 1 H) 7.22 (t, J = 7.43 Hz, 1 H)7.48-7.78 (m, 5 H) 7.83-8.06 (m, 3H) 8.55 (d, J = 2.35 Hz, 1 H) 8.61 (d,J = 2.35 Hz, 1 H). 5.20

(400 MHz, DMSO-d₆) 1.46 (s, 9 H) 3.31 (br. s., 2 H) 3.59 (t, J = 5.28Hz, 2 H) 4.08 (br. s., 2 H) 4.20-4.32 (m, 2 H) 4.38-4.59 (m, 3 H) 5.92(br. s., 1 H) 6.78 (d, J = 9.00 Hz, 1 H) 7.21 (t, J = 6.75 Hz, 1 H)7.46- 7.61 (m, 2 H) 7.71 (d, J = 7.82 Hz, 1 H) 8.04 (d, J = 8.80 Hz, 1H) 8.52 (d, J = 2.35 Hz, 1 H) 8.56 (d, J = 2.35 Hz, 1 H). 5.21

(400 MHz, CHLOROFORM-d) 4.38-4.54 (m, 5 H) 6.63 (d, J = 9.00 Hz, 1 H)7.19-7.24 (m, 1 H) 7.36- 7.42 (m, 1 H) 7.44-7.55 (m, 4 H) 7.57-7.63 (m,2 H) 7.66 (d, J = 7.63 Hz, 2 H) 7.69-7.77 (m, 3 H) 7.87 (d, J = 8.80 Hz,1 H) 8.56 (d, J = 2.54 Hz, 1 H) 8.60 (d, J = 2.35 Hz, 1 H). 5.22

(400 MHz, CHLOROFORM-d) 4.26-4.38 (m, 1 H) 4.41-4.54 (m, 4 H) 6.64 (d, J= 9.00 Hz, 1 H) 7.20- 7.25 (m, 1 H) 7.41-7.49 (m, 2 H) 7.51-7.58 (m, 1H) 7.62 (d, J = 7.82 Hz, 1 H) 7.73 (d, J = 8.41 Hz, 1 H) 7.80 (t, J =7.34 Hz, 1 H) 7.90 (d, J = 8.80 Hz, 1 H) 8.58 (d, J = 2.15 Hz, 1 H) 8.67(d, J = 2.15 Hz, 1 H). 5.23

(400 MHz, CHLOROFORM-d) 4.26-4.37 (m, 1 H) 4.40-4.53 (m, 4 H) 6.65 (s, 1H) 7.20-7.25 (m, 1 H) 7.40 (t, J = 8.51 Hz, 1 H) 7.51-7.58 (m, 1 H) 7.62(d, J = 7.82 Hz, 1 H) 7.73 (d, J = 8.41 Hz, 1 H) 7.75- 7.81 (m, 1 H)7.86 (dd, J = 5.97, 2.25 Hz, 1 H) 7.90 (d, J = 8.80 Hz, 1 H) 8.56 (d, J= 2.35 Hz, 1 H) 8.65 (d, J = 2.15 Hz, 1 H). 5.24

(400 MHz, CHLOROFORM-d) 2.98-3.22 (m, 6 H) 4.30-4.54 (m, 5 H) 6.63 (d, J= 8.80 Hz, 1 H) 7.22 (t, J = 7.14 Hz, 1 H) 7.49-7.64 (m, 6 H) 7.72 (d, J= 8.41 Hz, 1 H) 7.87 (d, J = 9.00 Hz, 1 H) 8.55 (d, J = 2.35 Hz, 1 H)8.61 (d, J = 2.35 Hz, 1 H). 5.25

(400 MHz, CHLOROFORM-d) 3.82 (s, 3 H) 4.04- 4.56 (m, 5 H) 6.61 (d, J =8.80 Hz, 1 H) 7.02 (d, J = 8.41 Hz, 1 H) 7.12 (t, J = 7.43 Hz, 1 H) 7.21(t, J = 7.43 Hz, 1 H) 7.37 (dd, J = 7.53, 1.47 Hz, 1 H) 7.43-7.55 (m, 2H) 7.59 (d, J = 7.82 Hz, 1 H) 7.72 (d, J = 8.41 Hz, 1 H) 7.85 (d, J =8.80 Hz, 1 H) 8.53 (d, J = 2.54 Hz, 1 H) 8.58 (d, J = 2.35 Hz, 1 H).5.26

(400 MHz, DMSO-d₆) 4.22-4.45 (m, 5 H) 6.76 (d, J = 8.61 Hz, 1 H) 7.22(t, J = 6.85 Hz, 1 H) 7.46-7.60 (m, 2 H) 7.71 (d, J = 7.82 Hz, 1 H)7.78-7.85 (m, 1 H) 7.89-7.98 (m, 3 H) 8.03 (d, J = 9.00 Hz, 1 H) 8.68(d, J = 2.35 Hz, 1 H) 8.74 (d, J = 2.35 Hz, 1 H). 5.27

(400 MHz, DMSO-d₆) 1.37 (t, J = 6.85 Hz, 3 H) 4.12 (q, J = 7.04 Hz, 2 H)4.23-4.52 (m, 5 H) 6.77 (d, J = 9.00 Hz, 1 H) 7.06-7.15 (m, 3 H)7.19-7.27 (m, 1 H) 7.42-7.61 (m, 3 H) 7.71 (d, J = 7.82 Hz, 1 H) 8.04(d, J = 8.61 Hz, 1 H) 8.63 (d, J = 2.35 Hz, 1 H) 8.68 (d, J = 2.35 Hz, 1H). 5.28

(400 MHz, DMSO-d₆) 2.68 (s, 3 H) 4.23-4.47 (m, 5 H) 6.75 (d, J = 9.00Hz, 1 H) 7.17-7.24 (m, 1 H) 7.47-7.59 (m, 2 H) 7.67-7.78 (m, 2 H) 7.87(d, J = 7.43 Hz, 1 H) 8.02 (d, J = 9.00 Hz, 1 H) 8.09-8.16 (m, 2 H) 8.67(d, J = 2.35 Hz, 1 H) 8.72 (d, J = 2.35 Hz, 1 H) 5.29

(400 MHz, DMSO-d₆) 4.20-4.45 (m, 5 H) 4.62 (d, J = 5.48 Hz, 2 H) 5.35(t, J = 5.67 Hz, 1 H) 6.75 (d, J = 9.00 Hz, 1 H) 7.21 (t, J = 7.24 Hz, 1H) 7.42-7.60 (m, 6 H) 7.70 (d, J = 8.22 Hz, 1 H) 8.03 (d, J = 8.61 Hz, 1H) 8.63 (d, J = 2.35 Hz, 1 H) 8.67 (d, J = 2.35 Hz, 1 H). 5.30

(400 MHz, DMSO-d₆) 4.23-4.47 (m, 5 H) 6.76 (d, J = 9.00 Hz, 1 H) 7.23(t, J = 7.24 Hz, 1 H) 7.48-7.66 (m, 5 H) 7.67-7.75 (m, 2 H) 8.01-8.09(m, 1 H) 8.65-8.68 (m, 1 H) 8.71-8.75 (m, 1 H). 5.31

(400 MHz, DMSO-d₆) 4.15-4.44 (m, 5 H) 5.21 (s, 2 H) 6.73 (d, J = 9.00Hz, 1 H) 7.11-7.25 (m, 4 H) 7.28-7.34 (m, 1 H) 7.41 (t, J = 7.63 Hz, 2H) 7.45- 7.59 (m, 5 H) 7.70 (d, J = 7.82 Hz, 1 H) 8.02 (d, J = 9.00 Hz,1 H) 8.63 (d, J = 2.35 Hz, 1 H) 8.67 (d, J = 2.35 Hz, 1 H) 5.32

(400 MHz, DMSO-d₆) 0.57-0.64 (m, 2 H) 0.69- 0.77 (m, 2 H) 2.89 (tq, J =7.34, 3.98 Hz, 1 H) 4.22- 4.45 (m, 5 H) 6.75 (d, J = 9.00 Hz, 1 H) 7.21(t, J = 7.43 Hz, 1 H) 7.47-7.59 (m, 2 H) 7.61-7.67 (m, 1 H) 7.72 (dd, J= 14.87, 7.82 Hz, 2 H) 7.93-8.08 (m, 3 H) 8.57 (d, J = 3.91 Hz, 1 H)8.66 (d, J = 2.35 Hz, 1 H) 8.71 (d, J = 2.35 Hz, 1 H) 5.33

(400 MHz, DMSO-d₆) 2.70 (s, 6 H) 4.25-4.43 (m, 5 H) 6.72-6.78 (m, 1 H)7.17-7.25 (m, 1 H) 7.47- 7.59 (m, 2 H) 7.70 (d, J = 7.82 Hz, 1 H)7.82-7.88 (m, 1 H) 7.90-7.98 (m, 3 H) 8.03 (d, J = 8.61 Hz, 1 H) 8.68(d, J = 2.35 Hz, 1 H) 8.74 (d, J = 2.74 Hz, 1 H) 5.34

(400 MHz, DMSO-d₆) 1.38 (t, J = 7.04 Hz, 3 H) 4.13 (q, J = 6.78 Hz, 2 H)4.22-4.29 (m, 2 H) 4.35 (t, J = 8.02 Hz, 2 H) 4.41-4.51 (m, 1 H) 6.76(d, J = 9.00 Hz, 1 H) 7.05-7.12 (m, 2 H) 7.19-7.25 (m, 1 H) 7.48-7.59(m, 4 H) 7.71 (d, J = 7.82 Hz, 1 H) 8.04 (d, J = 9.00 Hz, 1 H) 8.59-8.61(m, 1 H) 8.61-8.63 (m, 1 H) 5.35

(400 MHz, DMSO-d₆) 4.19-4.47 (m, 5 H) 4.62 (d, J = 5.87 Hz, 2 H) 5.33(t, J = 5.67 Hz, 1 H) 6.75 (d, J = 9.00 Hz, 1 H) 7.21 (t, J = 7.04 Hz, 1H) 7.47-7.59 (m, 6 H) 7.70 (d, J = 7.82 Hz, 1 H) 8.03 (d, J = 9.00 Hz, 1H) 8.63 (d, J = 2.74 Hz, 1 H) 8.66 (d, J = 2.74 Hz, 1 H) 5.36

(400 MHz, DMSO-d₆) 0.95 (t, J = 7.43 Hz, 3 H) 1.67 (sxt, J = 7.43 Hz, 2H) 2.66 (t, J = 7.63 Hz, 2 H) 4.23- 4.47 (m, 5 H) 6.76 (d, J = 9.00 Hz,1 H) 7.20-7.26 (m, 1 H) 7.38 (d, J = 7.82 Hz, 2 H) 7.47-7.61 (m, 4 H)7.72 (d, J = 7.43 Hz, 1 H) 8.05 (d, J = 9.00 Hz, 1 H) 8.62 (d, J = 2.35Hz, 1 H) 8.65 (d, J = 2.35 Hz, 1 H) 5.37

(400 MHz, DMSO-d₆) 1.26 (t, J = 7.43 Hz, 3 H) 2.72 (q, J = 7.56 Hz, 2 H)4.22-4.50 (m, 5 H) 6.76 (d, J = 9.00 Hz, 1 H) 7.18-7.27 (m, 1 H) 7.40(d, J = 8.22 Hz, 2 H) 7.47-7.61 (m, 4 H) 7.71 (d, J = 7.82 Hz, 1 H) 8.04(d, J = 9.00 Hz, 1 H) 8.62 (d, J = 2.35 Hz, 1 H) 8.65 (d, J = 2.74 Hz, 1H) 5.38

(400 MHz, DMSO-d₆) 3.01 (s, 6 H) 4.17-4.55 (m, 5 H) 6.76 (d, J = 9.00Hz, 1 H) 6.86 (d, J = 9.00 Hz, 2 H) 7.16-7.25 (m, 1 H) 7.42-7.61 (m, 4H) 7.70 (d, J = 7.43 Hz, 1 H) 8.02 (d, J = 9.00 Hz, 1 H) 8.51-8.58 (m, 2H) 5.39

(400 MHz, DMSO-d₆) 4.28-4.48 (m, 5 H) 6.80 (d, J = 9.00 Hz, 1 H)7.22-7.30 (m, 1 H) 7.52-7.62 (m, 4 H) 7.74 (d, J = 9.00 Hz, 3 H) 8.09(d, J = 8.61 Hz, 1 H) 8.66 (d, J = 2.35 Hz, 1 H) 8.72 (d, J = 2.35 Hz, 1H) 5.40

(400 MHz, DMSO-d₆) 1.33 (d, J = 6.26 Hz, 6 H) 4.20-4.52 (m, 5 H) 4.73(dt, J = 12.03, 5.92 Hz, 1 H) 6.78 (d, J = 9.00 Hz, 1 H) 7.08 (d, J =8.61 Hz, 2 H) 7.24 (t, J = 6.85 Hz, 1 H) 7.46-7.62 (m, 4 H) 7.72 (d, J =8.22 Hz, 1 H) 8.06 (d, J = 9.00 Hz, 1 H) 8.59-8.61 (m, 1 H) 8.61-8.63(m, 1 H) 5.41

(400 MHz, DMSO-d₆) 1.77 (s, 6 H) 4.23-4.46 (m, 5 H) 6.75 (d, J = 9.00Hz, 1 H) 7.21 (t, J = 7.24 Hz, 1 H) 7.48-7.59 (m, 2 H) 7.62-7.76 (m, 5H) 8.03 (d, J = 8.61 Hz, 1 H) 8.65 (d, J = 2.35 Hz, 1 H) 8.69 (d, J =2.35 Hz, 1 H) 5.42

(400 MHz, DMSO-d₆) 2.89-3.02 (m, 4 H) 3.61- 3.75 (m, 4 H) 4.22-4.48 (m,5 H) 6.74 (d, J = 8.61 Hz, 1 H) 7.17-7.24 (m, 1 H) 7.47-7.61 (m, 2 H)7.70 (d, J = 7.82 Hz, 1 H) 7.84-7.97 (m, 4 H) 8.02 (d, J = 9.00 Hz, 1 H)8.69 (d, J = 2.35 Hz, 1 H) 8.75 (d, J = 2.35 Hz, 1 H) 5.43

(400 MHz, DMSO-d₆) 1.41 (d, J = 3.91 Hz, 2 H) 1.57 (d, J = 4.69 Hz, 4 H)2.99 (t, J = 5.28 Hz, 4 H) 4.20-4.47 (m, 5 H) 6.74 (d, J = 9.00 Hz, 1 H)7.18- 7.25 (m, 1 H) 7.48-7.58 (m, 2 H) 7.70 (d, J = 7.82 Hz, 1 H)7.81-7.88 (m, 2 H) 7.88-7.95 (m, 2 H) 8.02 (d, J = 9.00 Hz, 1 H) 8.68(d, J = 2.35 Hz, 1 H) 8.74 (d, J = 2.35 Hz, 1 H)

Example 6.1 (R- &S-)-2-(3-(3-(3-(PYRIDIN-3-YL)PYRROLIDIN-1-YL)PYRAZIN-2-YL)AZETIDIN-1-YL)QUINOLINE

To a 3 mL vial was added2-(3-(3-chloropyrazin-2-yl)azetidin-1-yl)quinoline (0.04000 g, 0.135mmol), 3-(pyrrolidin-3-yl)pyridine (commerically available at ArrayBiopharma, 0.040 g, 0.270 mmol), and triethylamine (commericallyavailable at Sigma Aldrich, 0.038 ml, 0.270 mmol) in DMSO (SolventVolume: 0.449 ml) and the reaction was stirred at 110° C. overnight.Upon completion, the reaction was filtered into a 24 well plate andpurified by reverse phase purification using the following conditions:(Instrumentation: MS—Waters SQ; UV—Waters 2487 or Waters PD; Solvents:A: Water w/0.1% NH₄OH B: Acetonitrile w/0.1% NH₄OH; Column: PhenomenexGemini-NX C18 110A 5 um 21×100; Flow Rate: 44 mL/min. 10 min Method,variable gradient over 8 mins.)

The following Table 18A lists compounds of Examples 6.1 to 6.60, whichwere made analogous to Scheme 6 by using the appropriate materials andreaction conditions, which are listed in Table 18B. The NMR data of theExamples are listed in Table 18C.

TABLE 18A EXAMPLES 6.1 TO 6.60 ESI-MS Ex. # Structure Chemical Name(M + 1) IC₅₀ (μM) 6.1

(R- & S-)-2-(3-(3-(3-(pyridin- 3-yl)pyrrolidin-1-yl)pyrazin-2-yl)azetidin-1-yl)quinoline 409.0 0.001 6.2

(R- & S)-2-(3-(3-(3- phenethylpyrrolidin-1- yl)pyrazin-2-yl)azetidin-1-yl)quinoline 436 0.010 6.3

(R- & S-)-2-(3-(3-(3- benzylpyrrolidin-1-yl)pyrazin-2-yl)azetidin-1-yl)quinoline 422 0.005 6.4

(R)-N,N-dimethyl-1-(3-(1- (quinolin-2-yl)azetidin-3-yl)pyrazin-2-yl)pyrrolidin-3- amine 375 0.097 6.5

(R- & S-)-tert-butyl methyl(1- (3-(1-(quinolin-2-yl)azetidin-3-yl)pyrazin-2-yl)pyrrolidin-3- yl)carbamate 461 0.002 6.6

(R- & S-)-N,N-dimethyl-1-(3- (1-(quinolin-2-yl)azetidin-3-yl)pyrazin-2-yl)pyrrolidin-3- amine 375 0.061 6.7

2-(3-(3-(3- azabicyclo[3.1.0]hexan-3- yl)pyrazin-2-yl)azetidin-1-yl)quinoline 344 0.003 6.8

(R- & S-)-2-(3-(3-(3- (phenylsulfonyl)pyrrolidin-1-yl)pyrazin-2-yl)azetidin-1- yl)quinoline 472 0.008 6.9

(R- & S-)-3-methyl-5-(1-(3-(1- (quinolin-2-yl)azetidin-3-yl)pyrazin-2-yl)pyrrolidin-3- yl)-1,2,4-oxadiazole 414 0.001 6.10

(R)-1-(3-(1-(quinolin-2- yl)azetidin-3-yl)pyrazin-2- yl)pyrrolidin-3-ol348 0.007 6.11

(R- & S-)-2-(3-(3-(3-(pyridin- 4-yl)pyrrolidin-1-yl)pyrazin-2-yl)azetidin-1-yl)quinoline 409 0.001 6.12

2-(3-(3-(pyrrolidin-1- yl)pyrazin-2-yl)azetidin-1- yl)quinoline 3320.003 6.13

(3aR,6aS)-tert-butyl 5-(3-(1- (quinolin-2-yl)azetidin-3- yl)pyrazin-2-yl)hexahydropyrrolo[3,4- c]pyrrole-2(1H)-carboxylate 473 0.001 6.14

tert-butyl 5-(3-(1-(quinolin-2- yl)azetidin-3-yl)pyrazin-2-yl)hexahydropyrrolo[3,4- c]pyrrole-2(1H)-carboxylate 473 0.003 6.15

tert-butyl 4-(3-(1-(quinolin-2- yl)azetidin-3-yl)pyrazin-2-yl)-1,4-diazepane-1-carboxylate 461.1 0.225 6.16

(R)-(1-(3-(1-(quinolin-2- yl)azetidin-3-yl)pyrazin-2-yl)pyrrolidin-3-yl)methanol 362 0.006 6.17

(R- & S-)-2-(3-(3-(3- (methylsulfonyl)pyrrolidin-1-yl)pyrazin-2-yl)azetidin-1- yl)quinoline 410 0.033 6.18

(S)-(1-(3-(1-(quinolin-2- yl)azetidin-3-yl)pyrazin-2-yl)pyrrolidin-3-yl)methanol 362 0.006 6.19

(R)-tert-butyl 1-(3-(1- (quinolin-2-yl)azetidin-3-yl)pyrazin-2-yl)pyrrolidin-3- ylcarbamate 447.0 0.021 6.20

(S)-2-(3-(3-(3-fluoropyrrolidin- 1-yl)pyrazin-2-yl)azetidin-1-yl)quinoline 350.0 0.023 6.21

2-(3-(3-(3,3-difluoropyrrolidin- 1-yl)pyrazin-2-yl)azetidin-1-yl)quinoline 368 0.01575 6.22

2-(3-(3-(4-isopropyl-1,4- diazepan-1-yl)pyrazin-2-yl)azetidin-1-yl)quinoline 403 0.655 6.23

(1R,5R)-3-(3-(1-(quinolin-2- yl)azetidin-3-yl)pyrazin-2-yl)-3-azabicyclo[3.2.2]nonane 386 0.035 6.24

2-(3-(3-(azepan-1-yl)pyrazin-2- yl)azetidin-1-yl)quinoline 360 0.0036.25

2-(3-(3-(4-methyl-1,4- diazepan-1-yl)pyrazin-2-yl)azetidin-1-yl)quinoline 375 0.233 6.26

3-(3-(1-(quinolin-2-yl)azetidin- 3-yl)pyrazin-2-yl)-3-azabicyclo[3.2.2]nonane 386 0.035 6.27

1-(4-(3-(1-(quinolin-2- yl)azetidin-3-yl)pyrazin-2-yl)-1,4-diazepan-1-yl)ethanone 403 0.01607 6.28

(R- & S-)-2-(3-(3-(3- phenylpyrrolidin-1-yl)pyrazin-2-yl)azetidin-1-yl)quinoline 408 0.0050 6.29

(3S,4S)-1-(3-(1-(quinolin-2- yl)azetidin-3-yl)pyrazin-2-yl)pyrrolidine-3,4-diol 364 0.085 6.30

N-(4-methoxybenzyl)-3-(1- (quinolin-2-yl)azetidin-3- yl)pyrazin-2-amine398 0.189 6.31

(1R,4R)-5-(3-(1-(quinolin-2- yl)azetidin-3-yl)pyrazin-2-yl)- 2-oxa-5-azabicyclo[2.2.1]heptane 360 0.01545 6.32

(R- & S-)-2-(1-(3-(1-(quinolin- 2-yl)azetidin-3-yl)pyrazin-2-yl)pyrrolidin-3-yl)thiazole 415 0.0871 6.33

(S)-(1-(3-(1-(quinolin-2- yl)azetidin-3-yl)pyrazin-2-yl)pyrrolidin-2-yl)methanol 362 0.01457 6.34

((2S,4S)-4-fluoro-1-(3-(1- (quinolin-2-yl)azetidin-3-yl)pyrazin-2-yl)pyrrolidin-2- yl)methanol 380 0.02989 6.35

(R)-2-(3-(3-(2- (methoxymethyl)pyrrolidin-1- yl)pyrazin-2-yl)azetidin-1-yl)quinoline 362 0.81150 6.36

2-(3-(3- (hexahydrocyclopenta[c]pyrrol- 2(1H)-yl)pyrazin-2-yl)azetidin-1-yl)quinoline 372 0.00396 6.37

(R- & S-)-2-(3-(3-(3- isobutylpyrrolidin-1- yl)pyrazin-2-yl)azetidin-1-yl)quinoline 388 0.02193 6.38

2-(3-(3-(3,3- dimethylpyrrolidin-1- yl)pyrazin-2-yl)azetidin-1-yl)quinoline 360 0.01275 6.39

(R- & S-)-2-(3-(3-(3- (methoxymethyl)pyrrolidin-1-yl)pyrazin-2-yl)azetidin-1- yl)quinoline 376 0.00666 6.40

2-(3-(3-(4- (trifluoromethyl)piperidin-1- yl)pyrazin-2-yl)azetidin-1-yl)quinoline 414 0.0065 6.41

1-(3-(1-(quinolin-2-yl)azetidin- 3-yl)pyrazin-2-yl)piperidine-4-carbonitrile 371 0.00013 6.42

2-(3-(3-(4,4-difluoropiperidin- 1-yl)pyrazin-2-yl)azetidin-1-yl)quinoline 382 0.0086 6.43

4-(3-(1-(quinolin-2-yl)azetidin- 3-yl)pyrazin-2-yl)morpholine 348 0.01476.44

2-(3-(3-(4-fluoropiperidin-1- yl)pyrazin-2-yl)azetidin-1- yl)quinoline364 0.0014 6.45

2-(3-(3-(3-methoxyazetidin-1- yl)pyrazin-2-yl)azetidin-1- yl)quinoline348 0.021 6.46

2-(3-(3-(3,3-difluoroazetidin-1- yl)pyrazin-2-yl)azetidin-1-yl)quinoline 354 0.027 6.47

4-methyl-1-(3-(1-(quinolin-2- yl)azetidin-3-yl)pyrazin-2-yl)piperidin-4-ol 376 0.0097 6.48

1-(3-(1-(quinolin-2-yl)azetidin- 3-yl)pyrazin-2-yl)-1H-pyrazole-4-carbonitrile 354 0.066 6.49

2-(3-(3-(4-methyl-1H-pyrazol- 1-yl)pyrazin-2-yl)azetidin-1- yl)quinoline343 0.020 6.50

tert-butyl (1-(3-(1-(quinolin-2- yl)azetidin-3-yl)pyrazin-2-yl)azetidin-3-yl)carbamate 433 0.0056 6.51

2,2-dimethyl-4-(3-(1-(quinolin- 2-yl)azetidin-3-yl)pyrazin-2-yl)morpholine 376 0.006 6.52

2-(3-(3-(4-methyl-1H- imidazol-1-yl)pyrazin-2-yl)azetidin-1-yl)quinoline 343 0.005 6.53

1-(3-(1-(quinazolin-2- yl)azetidin-3-yl)pyrazin-2-yl)piperidine-4-carbonitrile 372 0.0015 6.54

(1-(3-(1-(quinolin-2- yl)azetidin-3-yl)pyrazin-2-yl)-1H-pyrazol-4-yl)methanol 359 0.091 6.55

(1-(3-(1-(quinolin-2- yl)azetidin-3-yl)pyrazin-2-yl)-1H-imidazol-4-yl)methanol 359 0.270 6.56

1-methyl-4-(3-(1-(quinolin-2- yl)azetidin-3-yl)pyrazin-2-yl)piperazin-2-one 375 0.0022 6.57

N-(2,6-dimethylphenyl)-1-(3- (1-(quinolin-2-yl)azetidin-3-yl)pyrazin-2-yl)piperidine-3- carboxamide 493 0.010 6.58

(S)-tert-butyl (1-(3-(1- (quinolin-2-yl)azetidin-3-yl)pyrazin-2-yl)piperidin-3- yl)carbamate 461 0.013 6.59

(4-(cyclopropylmethyl)-1-(3- (1-(quinolin-2-yl)azetidin-3-yl)pyrazin-2-yl)piperidin-4- yl)methanol 430 0.004 6.60

2-(3-(3-((1R,5S)-8-methyl-3,8- diazabicyclo[3.2.1]octan-3-yl)pyrazin-2-yl)azetidin-1- yl)quinoline 387 >10

TABLE 18B STARTING MATERIALS AND REACTION CONDITION FOR PREPARATION OFEXAMPLES 6.1 TO 6.60. Unless otherwise stated, all starting materialsare commercially available from common vendors. Key StartingPurification Ex. # Material(s) Key Starting Material(s) ReactionCondition Condition* 6.1

TEA, DMSO, 110° C. A 6.2

TEA, DMSO, 110° C. A 6.3

TEA, DMSO, 110° C. A 6.4

TEA, DMSO, 110° C. A 6.5

TEA, DMSO, 110° C. A 6.6

TEA, DMSO, 110° C. A 6.7

TEA, DMSO, 110° C. A 6.8

TEA, DMSO, 110° C. A 6.9

TEA, DMSO, 110° C. A 6.10

TEA, DMSO, 110° C. A 6.11

TEA, DMSO, 110° C. A 6.12

TEA, DMSO, 110° C. A 6.13

TEA, DMSO, 110° C. A 6.14

TEA, DMSO, 110° C. A 6.15

TEA, DMSO, 110° C. A 6.16

TEA, DMSO, 110° C., D 6.17

TEA, DMSO, 110° C. A 6.18

TEA, DMSO, 110° C. A 6.19

TEA, DMSO, 110° C. A 6.20

K₂CO₃, DMSO, 110° C. A 6.21

K₂CO₃, DMSO, 110° C. B 6.22

K₂CO₃, DMSO, 110° C. A 6.23

K₂CO₃, DMSO, 110° C. A 6.24

K₂CO₃, DMSO, 110° C. A 6.25

K₂CO₃, DMSO, 110° C. A 6.26

K₂CO₃, DMSO, 110° C. A 6.27

K₂CO₃, DMSO, 110° C. A 6.28

K₂CO₃, DMSO, 110° C. A 6.29

K₂CO₃, DMSO, 110° C. A 6.30

K₂CO₃, DMSO, 110° C. C 6.31

K₂CO₃, DMSO, 110° C. A 6.32

K₂CO₃, DMSO, 110° C. A 6.33

K₂CO₃, DMSO, 110° C. A 6.34

K₂CO₃, DMSO, 110° C. A 6.35

K₂CO₃, DMSO, 110° C. A 6.36

K₂CO₃, DMSO, 110° C. A 6.37

K₂CO₃, DMSO, 110° C. A 6.38

K₂CO₃, DMSO, 110° C. A 6.39

K₂CO₃, DMSO, 110° C. A 6.40

TEA, DMSO, 110° C. B 6.41

TEA, DMSO, 110° C. B 6.42

TEA, DMSO, 110° C. B 6.43

TEA, DMSO, 110° C. B 6.44

TEA, DMSO, 110° C. B 6.45

TEA, DMSO, 110° C. B 6.46

TEA, DMSO, 110° C. B 6.47

1. HCl 2. Et₃N, DMSO, 110° C. B 6.48

Cs₂CO₃, DMSO, 110° C. B 6.49

Cs₂CO₃, DMSO, 110° C. B 6.50

TEA, DMSO, 110° C. B 6.51

TEA, DMSO, 110° C. B 6.52

Cs₂CO₃, DMSO, 110° C. B 6.53

TEA, DMSO, 110° C. B 6.54

allylchloro[1,3- bis(2,6-di-i- propylphenyl)-4,5- dihydroimidazol-2-ylidene]palladium(II), Cs₂CO₃, Dioxane, 135° C., μW, 30 min E 6.55

TEA, DMSO, 110° C. B 6.56

TEA, DMSO, 110° C. B 6.57

TEA, DMSO, 110° C. B 6.58

TEA, DMSO, 110° C. B 6.59

TEA, DMSO, 110° C. B 6.60

K₂CO₃, DMSO, 110° C. C *Purification Conditions: Method A—reverse phasepurification using the following conditions: (Instrumentation: MS—WatersSQ; UV—Waters 2487 or Waters PD; Solvents: A: Water w/0.1% NH₄OH B:Acetonitrile w/0.1% NH₄OH; Column: Phenomenex Gemini-NX C18 110A 5 um 21× 100; Flow Rate: 44 mL/min. 10 min Method, variable gradient over 8mins). Method B—purification by silica gel chromatography: (Biotage 50 gSNAP HP-silica column, eluting with a gradient of EtOAc in hexane).Method C—reverse-phase HPLC (Gilson; Gemini-NX 10 m C18 110A AXIA, 100 ×50 mm column) eluting with 0.1% TFA-H₂O:0.1% TFA CH₃CN (9:1 → 1:9). Thefractions containing the desired product were combined and concentratedin vacuo. The residue was dissolved in DCM and loaded onto aSi-Carbonate cartridge (Silicycle) eluting with DCM. Method D—Productprecipitated out of solution. Method E—purification by silica gelchromatography eluting with a gradient of MeOH in DCM.

TABLE 18C 1H NMR δ (PPM) DATA FOR EXAMPLES 6.1 TO 6.60 Ex. # StructureNMR 6.1 

(400 MHz, DMSO-d₆) 2.09 (quin, J = 9.88 Hz, 1H) 2.38 (td, J = 5.87, 2.35Hz, 1H) 3.44-3.56 (m, 1H) 3.55-3.66 (m, 2H) 3.76 (td, J = 9.78, 6.65 Hz,1H) 3.85 (dd, J = 9.78, 7.43 Hz, 1H) 4.27-4.49 (m, 5H) 6.78 (d, J = 9.00Hz, 1H) 7.16-7.25 (m, 1H) 7.39 (dd, J = 7.82, 4.69 Hz, 1H) 7.46-7.59 (m,2H) 7.70 (d, J = 7.82 Hz, 1H) 7.77-7.85 (m, 1H) 7.93-8.06 (m, 3H) 8.48(dd, J = 4.69, 1.56 Hz, 1H) 8.60 (d, J = 2.35 Hz, 1H) 6.2 

(400 MHz, DMSO-d₆) 1.54-1.68 (m, 1H) 1.76 (q, J = 6.91 Hz, 2H) 2.02-2.24(m, 2H) 2.68 (t, J = 7.63 Hz, 2H) 3.24 (t, J = 9.19 Hz, 1H) 3.42-3.60(m, 3H) 4.34 (s, 4H) 4.45 (s, 1H) 6.78 (d, J = 9.00 Hz, 1H) 7.13-7.34(m, 6H) 7.47-7.59 (m, 2H) 7.71 (d, J = 8.22 Hz, 1H) 7.91 (d, J = 2.74Hz, 1H) 7.97 (d, J = 2.74 Hz, 1H) 8.03 (d, J = 9.00 Hz, 1H) 6.3 

(400 MHz, DMSO-d₆) 1.60-1.72 (m, 1H) 1.99 (dd, J = 10.56, 5.48 Hz, 1H)2.75 (dd, J = 7.24, 2.54 Hz, 2H) 3.23-3.30 (m, 1H) 3.45 (dd, J = 10.17,7.04 Hz, 1H) 3.50-3.59 (m, 2H) 4.25-4.44 (m, 5H) 6.77 (d, J = 8.61 Hz,1H) 7.15-7.25 (m, 2H) 7.24-7.29 (m, 2H) 7.29- 7.36 (m, 2H) 7.47-7.60 (m,2H) 7.70 (d, J = 7.82 Hz, 1H) 7.90 (d, J = 2.35 Hz, 1H) 7.96 (d, J =2.74 Hz, 1H) 8.03 (d, J = 9.00 Hz, 1H) 6.4 

(400 MHz, DMSO-d₆) 2.02-2.18 (m, 1H) 2.38 (qd, J = 6.00, 3.91 Hz, 1H)2.45-2.54 (m, 3H) 3.45-3.58 (m, 1H) 3.57-3.67 (m, 2H) 3.76 (td, J =9.78, 6.65 Hz, 1H) 3.86 (dd, J = 9.78, 7.43 Hz, 1H) 4.30-4.50 (m, 5H)6.78 (d, J = 9.00 Hz, 1H) 7.16-7.25 (m, 1H) 7.39 (dd, J = 7.82, 4.69 Hz,1H) 7.47-7.59 (m, 2H) 7.70 (d, J = 7.82 Hz, 1H) 7.82 (d, J = 7.82 Hz,1H) 7.95-8.06 (m, 3H) 8.48 (dd, J = 4.69, 1.56 Hz, 1H) 8.61 (d, J = 2.35Hz, 1H) 6.5 

(400 MHz, DMSO-d₆) 1.43 (s, 8H) 2.01-2.13 (m, 2H) 2.47-2.54 (m, 3H) 2.81(s, 3H) 3.46-3.60 (m, 4H) 4.29-4.40 (m, 4H) 4.40-4.49 (m, 1H) 6.79 (d, J= 8.61 Hz, 1H) 7.16-7.25 (m, 1H) 7.47-7.60 (m, 2H) 7.71 (d, J = 7.82 Hz,1H) 7.95-8.06 (m, 2H) 6.6 

(400 MHz, DMSO-d₆) 1.76 (quin, J = 10.07 Hz, 1H) 2.07-2.17 (m, 1H) 2.22(s, 5H) 2.64-2.77 (m, 1H) 3.17 (br. s., 1H) 3.41 (s, 1H) 3.44-3.67 (m,3H) 4.35 (dt, J = 8.70, 4.45 Hz, 3H) 4.41-4.51 (m, 1H) 6.79 (d, J = 9.00Hz, 1H) 7.17-7.25 (m, 1H) 7.47-7.60 (m, 2H) 7.71 (d, J = 7.43 Hz, 1H)7.96 (dd, J = 18.78, 2.74 Hz, 2H) 8.03 (d, J = 9.00 Hz, 1H) 6.7 

(400 MHz, DMSO-d₆) 0.30 (q, J = 4.30 Hz, 1H) 0.66 (td, J = 7.63, 4.69Hz, 1H) 1.59-1.70 (m, 2H) 3.46 (d, J = 10.17 Hz, 2H) 3.73 (d, J = 10.17Hz, 2H) 4.23-4.35 (m, 3H) 4.36-4.46 (m, 2H) 6.78 (d, J = 9.00 Hz, 1H)7.17-7.26 (m, 1H) 7.48-7.60 (m, 2H) 7.71 (d, J = 7.43 Hz, 1H) 7.97 (d, J= 2.35 Hz, 1H) 8.00 (d, J = 2.35 Hz, 1H) 8.03 (d, J = 9.00 Hz, 1H) 6.8 

(400 MHz, DMSO-d₆) 2.21-2.37 (m, 2H) 3.46-3.61 (m, 2H) 3.63-3.72 (m, 1H)3.80 (dd, J = 11.74, 5.87 Hz, 1H) 4.18-4.40 (m, 6H) 6.77 (d, J = 9.00Hz, 1H) 7.18- 7.26 (m, 1H) 7.48-7.56 (m, 1H) 7.55-7.61 (m, 1H) 7.67-7.75(m, 3H) 7.77-7.86 (m, 1H) 7.93-7.99 (m, 2H) 8.00-8.07 (m, 3H) 6.9 

(400 MHz, DMSO-d₆) 2.23-2.35 (m, 1H) 2.38 (s, 3H) 2.43-2.51 (m, 1H)3.61-3.74 (m, 2H) 3.79-3.88 (m, 1H) 3.88-3.99 (m, 2H) 4.33-4.48 (m, 5H)6.81 (d, J = 9.00 Hz, 1H) 7.24 (ddd, J = 7.92, 6.55, 1.56 Hz, 1H)7.51-7.63 (m, 2H) 7.74 (d, J = 7.43 Hz, 1H) 8.02- 8.04 (m, 1H) 8.04-8.08(m, 2H) 6.10

(400 MHz, DMSO-d₆) 1.88 (d, J = 3.52 Hz, 1H) 1.92- 2.04 (m, 1H) 3.25 (d,J = 10.95 Hz, 1H) 3.40-3.50 (m, 1H) 3.64-3.76 (m, 2H) 4.29-4.42 (m, 5H)4.42-4.51 (m, 1H) 4.97 (d, J = 3.13 Hz, 1H) 6.79 (d, J = 9.00 Hz, 1H)7.21 (t, J = 7.43 Hz, 1H) 7.48-7.60 (m, 2H) 7.71 (d, J = 7.43 Hz, 1H)7.91 (d, J = 2.74 Hz, 1H) 7.97 (d, J = 2.35 Hz, 1H) 8.03 (d, J = 9.00Hz, 1H) 6.11

(400 MHz, DMSO-d₆) 1.97-2.13 (m, 1H) 2.38 (dq, J = 8.95, 6.15 Hz, 1H)3.44-3.56 (m, 1H) 3.56-3.68 (m, 1H) 3.74 (td, J = 9.59, 7.04 Hz, 1H)3.85 (dd, J = 9.98, 7.24 Hz, 1H) 4.29-4.49 (m, 1H) 6.78 (d, J = 9.00 Hz,1H) 7.16-7.25 (m, 1H) 7.36-7.44 (m, 1H) 7.46-7.60 (m, 1H) 7.70 (d, J =7.04 Hz, 1H) 7.97 (d, J = 2.74 Hz, 1H) 7.99-8.06 (m, 1H) 8.49-8.56 (m,1H) 6.12

(400 MHz, DMSO-d₆) 1.91 (dt, J = 6.16, 3.37 Hz, 1H) 3.43-3.53 (m, 1H)4.31-4.44 (m, 1H) 6.78 (d, J = 9.00 Hz, 1H) 7.17-7.24 (m, 1H) 7.48-7.59(m, 1H) 7.70 (d, J = 7.82 Hz, 1H) 7.91 (d, J = 2.35 Hz, 1H) 7.97 (d, J =2.35 Hz, 1H) 8.03 (d, J = 9.00 Hz, 1H) 6.13

(400 MHz, DMSO-d₆) 1.41 (s, 9H) 2.95 (br. s., 2H) 3.17 (d, J = 5.09 Hz,1H) 3.40 (d, J = 3.91 Hz, 2H) 3.52 (br. s., 2H) 3.68 (dd, J = 10.37,7.24 Hz, 2H) 4.10 (q, J = 5.09 Hz, 1H) 4.30-4.46 (m, 5H) 6.77 (d, J =9.00 Hz, 1H) 7.16-7.26 (m, 1H) 7.46-7.59 (m, 2H) 7.70 (d, J = 7.82 Hz,1H) 7.93-8.06 (m, 3H) 6.14

(400 MHz, DMSO-d₆) 1.41 (s, 8H) 2.95 (br. s., 2H) 3.17 (d, J = 5.09 Hz,1H) 3.23 (d, J = 10.17 Hz, 2H) 3.40 (d, J = 3.91 Hz, 1H) 3.52 (br. s.,2H) 3.68 (dd, J = 10.56, 7.43 Hz, 2H) 4.10 (q, J = 4.96 Hz, 1H)4.31-4.47 (m, 5H) 6.77 (d, J = 9.00 Hz, 1H) 7.17-7.25 (m, 1H) 7.47-7.59(m, 2H) 7.71 (d, J = 7.43 Hz, 1H) 7.95-8.06 (m, 3H) 6.15

(400 MHz, DMSO-d₆) 1.36 (d, J = 19.56 Hz, 9H) 1.86-1.97 (m, 2H) 3.42(dd, J = 11.35, 5.67 Hz, 4H) 3.53 (br. s., 4H) 4.20-4.35 (m, 3H)4.42-4.50 (m, 2H) 6.81 (d, J = 8.80 Hz, 1H) 7.19-7.27 (m, 1H) 7.55 (dd,J = 6.65, 1.37 Hz, 1H) 7.58 (s, 1H) 7.73 (d, J = 7.43 Hz, 1H) 8.02-8.12(m, 3H) 6.16

(400 MHz, DMSO-d₆) 1.69 (dq, J = 12.18, 7.81 Hz, 1H) 1.99 (dq, J =12.10, 6.01 Hz, 1H) 2.29-2.42 (m, 1H) 3.32-3.37 (m, 1H) 3.38-3.56 (m,5H) 4.29-4.38 (m, 4H) 4.39-4.47 (m, 1H) 4.70 (t, J = 5.38 Hz, 1H) 6.78(d, J = 8.80 Hz, 1H) 7.16-7.25 (m, 1H) 7.47- 7.54 (m, 1H) 7.54-7.59 (m,1H) 7.70 (d, J = 7.63 Hz, 1H) 7.91 (d, J = 2.54 Hz, 1H) 7.97 (d, J =2.54 Hz, 1H) 8.03 (d, J = 8.80 Hz, 1H) 6.17

(400 MHz, DMSO-d₆) 2.34-2.45 (m, 1H) 2.95 (s, 3H) 3.51-3.61 (m, 1H)3.63-3.73 (m, 1H) 3.80- 3.92 (m, 2H) 4.29-4.40 (m, 1H) 4.40-4.53 (m, 3H)6.74 (d, J = 9.00 Hz, 1H) 7.21-7.29 (m, 1H) 7.52-7.59 (m, 1H) 7.60-7.65(m, 1H) 7.66-7.72 (m, 1H) 7.96-8.05 (m, 2H) 6.18

(400 MHz, ACETONITRILE-d₃) 1.66-1.79 (m, 1H) 1.96-2.09 (m, 1H) 2.43 (dt,J = 14.23, 7.07 Hz, 1H) 3.35 (dd, J = 10.17, 7.04 Hz, 1H) 3.48-3.61 (m,3H) 4.31-4.55 (m, 3H) 6.74 (d, J = 9.00 Hz, 1H) 7.21-7.30 (m, 1H)7.52-7.59 (m, 1H) 7.60-7.66 (m, 1H) 7.66-7.73 (m, 1H) 7.89 (d, J = 2.54Hz, 1H) 7.93 (d, J = 2.54 Hz, 1H) 7.99 (d, J = 9.00 Hz, 1H) 6.19

(400 MHz, DMSO-d₆) 1.41 (s, 9H) 1.86 (dq, J = 12.47, 6.41 Hz, 1H) 2.09(dq, J = 12.62, 6.49 Hz, 1H) 3.17 (d, J = 5.09 Hz, 1H) 3.45-3.55 (m, 1H)3.55-3.62 (m, 1H) 3.62-3.71 (m, 1H) 4.03-4.14 (m, 1H) 4.28-4.45 (m, 5H)6.78 (d, J = 9.00 Hz, 1H) 7.14-7.25 (m, 2H) 7.48-7.60 (m, 2H) 7.71 (d, J= 7.43 Hz, 1H) 7.91-8.00 (m, 2H) 8.04 (d, J = 9.00 Hz, 1H) 6.20

(400 MHz, DMSO-d₆) 1.99-2.30 (m, 2H) 3.48- 3.64 (m, 2H) 3.71-3.96 (m,2H) 4.30-4.42 (m, 4H) 4.45-4.55 (m, 1H) 5.32-5.52 (m, 1H) 6.78 (d, J =9.00 Hz, 1H) 7.17-7.25 (m, 1H) 7.48-7.60 (m, 2H) 7.70 (d, J = 7.43 Hz,1H) 7.95-8.06 (m, 3H) 6.21

(400 MHz, ACETONITRILE-d₃) (tt, J = 14.08, 7.24 Hz, 2H) 3.75 (t, J =7.24 Hz, 2H) 3.89 (t, J = 13.20 Hz, 2H) 4.27-4.38 (m, 1H) 4.40- 4.54 (m,4H) 6.77 (d, J = 8.80 Hz, 1H) 7.22-7.30 (m, 1H) 7.53-7.60 (m, 1H)7.60-7.65 (m, 1H) 7.67-7.74 (m, 1H) 8.00 (d, J = 8.80 Hz, 1H) 8.07 (dd,J = 16.63, 2.54 Hz, 2H) 6.22

(400 MHz, DMSO-d₆) 0.96 (d, J = 6.65 Hz, 6H) 1.79- 1.91 (m, 2H)2.45-2.54 (m, 1H) 2.58-2.65 (m, 2H) 2.70-2.77 (m, 2H) 2.86 (quin, J =6.55 Hz, 1H) 3.42- 3.50 (m, 4H) 4.16-4.33 (m, 3H) 4.37-4.47 (m, 2H) 6.78(d, J = 8.61 Hz, 1H) 7.16-7.26 (m, 1H) 7.46-7.60 (m, 2H) 7.70 (d, J =7.43 Hz, 1H) 7.98-8.06 (m, 3H) 6.23

(400 MHz, DMSO-d₆) 1.67 (d, J = 9.78 Hz, 1H) 1.83 (d, J = 7.82 Hz, 1H)2.11 (br. s., 1H) 3.31 (d, J = 4.69 Hz, 1H) 4.26-4.33 (m, 1H) 4.32-4.42(m, 1H) 4.43-4.51 (m, 1H) 6.79 (d, J = 9.00 Hz, 1H) 7.17-7.25 (m, 1H)7.48-7.60 (m, 1H) 7.71 (d, J = 7.43 Hz, 1H) 8.04 (d, J = 9.00 Hz, 1H)8.11 (d, J = 2.35 Hz, 1H) 8.15 (d, J = 2.35 Hz, 1H) 6.24

(400 MHz, DMSO-d₆) 1.53-1.62 (m, 4H) 1.79 (br. s., 4H) 3.42-3.48 (m, 5H)4.20-4.31 (m, 1H) 4.39 (t, J = 7.04 Hz, 2H) 4.46-4.55 (m, 2H) 6.85 (d, J= 9.00 Hz, 1H) 7.28 (t, J = 6.85 Hz, 1H) 7.54-7.65 (m, 2H) 7.76 (d, J =7.82 Hz, 1H) 8.03 (q, J = 2.35 Hz, 2H) 8.12 (d, J = 9.00 Hz, 1H) 6.25

(400 MHz, DMSO-d₆) 1.89-2.01 (m, 1H) 2.35 (s, 1H) 2.60-2.69 (m, 1H) 2.80(d, J = 3.52 Hz, 1H) 3.48 (br. s., 2H) 3.50-3.56 (m, 1H) 4.18-4.34 (m,1H) 4.37-4.47 (m, 1H) 6.78 (d, J = 8.61 Hz, 1H) 7.17-7.26 (m, 1H)7.47-7.60 (m, 1H) 7.71 (d, J = 7.43 Hz, 1H) 7.99-8.07 (m, 1H) 6.26

(400 MHz, DMSO-d₆) 1.66 (d, J = 9.78 Hz, 1H) 1.83 (d, J = 7.43 Hz, 1H)2.11 (br. s., 1H) 3.31 (d, J = 4.30 Hz, 1H) 4.26-4.33 (m, 1H) 4.33-4.42(m, 1H) 4.43-4.52 (m, 1H) 6.79 (d, J = 9.00 Hz, 1H) 7.18-7.26 (m, 1H)7.48-7.61 (m, 1H) 7.71 (d, J = 7.82 Hz, 1H) 8.04 (d, J = 9.00 Hz, 1H)8.11 (d, J = 2.35 Hz, 1H) 8.15 (d, J = 2.35 Hz, 1H) 6.27

(400 MHz, DMSO-d₆) 1.77-1.88 (m, 1H) 1.96 (s, 2H) 3.12-3.30 (m, 5H)3.40-3.61 (m, 6H) 3.66 (br. s., 1H) 4.18-4.36 (m, 2H) 4.41-4.52 (m, 1H)6.76-6.84 (m, 1H) 7.23 (t, J = 7.43 Hz, 1H) 7.48-7.62 (m, 1H) 7.72 (d, J= 7.82 Hz, 1H) 8.01- 8.14 (m, 2H) 6.28

(400 MHz, DMSO-d₆) 2.05 (quin, J = 9.98 Hz, 1H) 2.34 (qd, J = 5.93, 4.11Hz, 1H) 3.40-3.52 (m, 1H) 3.53- 3.65 (m, 2H) 3.68-3.86 (m, 2H) 4.29-4.49(m, 5H) 6.77 (d, J = 8.61 Hz, 1H) 7.16-7.29 (m, 2H) 7.30-7.41 (m, 4H)7.47-7.59 (m, 2H) 7.70 (d, J = 7.43 Hz, 1H) 7.91-8.06 (m, 3H) 6.29

(400 MHz, DMSO-d₆) 3.22 (d, J = 11.35 Hz, 2H) 3.85 (dd, J = 11.15, 3.72Hz, 2H) 4.02 (br. s., 2H) 4.26-4.42 (m, 4H) 4.50 (t, J = 6.06 Hz, 1H) ¹HNMR (400 MHz, DMSO-d₆) δ 5.15 (d, J = 2.35 Hz, 2H) 6.78 (d, J = 9.00 Hz,1H) 7.16-7.25 (m, 1H) 7.48-7.55 (m, 1H) 7.55-7.60 (m, 1H) 7.71 (d, J =7.82 Hz, 1H) 7.90 (d, J = 2.35 Hz, 1H) 7.96 (d, J = 2.74 Hz, 1H) 8.03(d, J = 9.00 Hz, 1H) 6.30

(400 MHz, DMSO-d₆) 3.74 (s, 3H) 4.18-4.27 (m, 1H) 4.28-4.36 (m, 2H)4.47-4.57 (m, 3H) 6.82 (d, J = 8.80 Hz, 1H) 6.89 (d, J = 8.61 Hz, 2H)7.06 (t, J = 5.97 Hz, 1H) 7.19-7.31 (m, 3H) 7.50-7.57 (m, 1H) 7.57-7.62(m, 1H) 7.69-7.76 (m, 2H) 7.88 (d, J = 2.74 Hz, 1H) 8.05 (d, J = 8.80Hz, 1H) 6.31

(400 MHz, DMSO-d₆) 1.81-1.88 (m, 1H) 1.88-1.94 (m, 1H) 3.21 (d, J = 9.39Hz, 1H) 3.73 (dd, J = 9.19, 1.37 Hz, 1H) 3.80 (dd, J = 7.63, 1.37 Hz,1H) 3.86 - ¹H NMR (400 MHz, DMSO-d₆) δ 3.92 (m, 1H) 4.17-4.27 (m, 1H)4.28-4.39 (m, 3H) 4.43-4.51 (m, 1H) 4.63 (s, 1H) 4.69 (s, 1H) 6.78 (d, J= 9.00 Hz, 1H) 7.17- 7.25 (m, 1H) 7.48-7.60 (m, 2H) 7.70 (d, J = 7.43Hz, 1H) 7.98-8.06 (m, 3H) 6.32

(400 MHz, DMSO-d₆) 1.92-2.11 (m, 3H) 3.40 (dd, J = 8.61, 3.52 Hz, 2H)3.94-4.04 (m, 1H) 4.36-4.48 (m, 4H) 4.50-4.58 (m, 1H) 5.68 (t, J = 7.04Hz, 1H) 6.80 (d, J = 9.00 Hz, 1H) 7.17-7.25 (m, 1H) 7.48 (d, J = 3.13Hz, 1H) 7.50-7.56 (m, 1H) 7.56-7.61 (m, 1H) 7.68 (d, J = 3.13 Hz, 1H)7.71 (d, J = 7.04 Hz, 1H) 7.98 (d, J = 2.74 Hz, 1H) 8.02-8.08 (m, 2H)6.33

(400 MHz, DMSO-d₆) 1.66-1.81 (m, 1H) 1.88 (d, J = 7.43 Hz, 1H) 1.94(ddd, J = 13.89, 7.04, 3.33 Hz, 1H) 2.00-2.10 (m, 1H) 3.21 (t, J = 7.24Hz, 1H) 3.47-3.56 (m, 1H) 3.65-3.76 (m, 1H) 4.25-4.37 (m, 5H) 4.47-4.56(m, 1H) 4.62 (t, J = 5.67 Hz, 1H) 6.77 (d, J = 9.00 Hz, 1H) 7.16-7.24(m, 1H) 7.52 (dd, J = 6.85, 1.37 Hz, 1H) 7.54-7.59 (m, 1H) 7.70 (d, J =7.43 Hz, 1H) 7.94-7.97 (m, 1H) 7.97-8.00 (m, 1H) 8.02 (d, J = 9.00 Hz,1H) 6.34

(400 MHz, DMSO-d₆) 2.17-2.38 (m, 2H) 3.33- 3.40 (m, 1H) 3.47-3.63 (m,2H) 3.95 (t, J = 13.11 Hz, 1H) 4.26-4.41 (m, 3H) 4.45-4.57 (m, 2H) 4.77(t, J = 5.48 Hz, 1H) 5.27-5.48 (m, 1H) 6.78 (d, J = 9.00 Hz, 1H) 7.22(t, J = 7.24 Hz, 1H) 7.53 (d, J = 6.65 Hz, 1H) 7.55-7.61 (m, 1H) 7.71(d, J = 7.82 Hz, 1H) 8.00-8.09 (m, 2H) 6.35

(400 MHz, DMSO-d₆) ppm 1.67-1.86 (m, 2H) 1.90-2.00 (m, 1H) 2.05-2.15 (m,1H) 3.15-3.26 (m, 4H) 3.47 (dd, J = 9.39, 3.91 Hz, 1H) 3.65-3.75 (m, 1H)4.22-4.36 (m, 4H) 4.44 (dd, J = 6.85, 4.11 Hz, 1H) 4.47-4.56 (m, 1H)6.76 (d, J = 9.00 Hz, 1H) 7.17- 7.24 (m, 1H) 7.47-7.54 (m, 1H) 7.55 (s,1H) 7.70 (d, J = 7.82 Hz, 1H) 7.96-8.06 (m, 2H) 6.36

(400 MHz, DMSO-d₆) 1.45-1.62 (m, 1H) 1.68-1.84 (m, 1H) 2.72 (br. s., 1H)3.15 (dd, J = 10.17, 3.52 Hz, 1H) 3.41 (br. s., 1H) 3.55 (dd, J = 10.76,7.63 Hz, 1H) 4.33 (d, J = 2.35 Hz, 2H) 4.44 (s, 1H) 6.79 (d, J = 9.00Hz, 1H) 7.21 (t, J = 7.04 Hz, 1H) 7.48-7.59 (m, 1H) 7.71 (d, J = 7.82Hz, 1H) 7.97-8.06 (m, 2H) 6.37

(400 MHz, DMSO-d₆) 0.92 (dd, J = 6.46, 2.93 Hz, 4H) 1.33 (t, J = 6.94Hz, 1H) 1.52 (quin, J = 9.93 Hz, 1H) 1.58-1.70 (m, 1H) 2.01-2.12 (m, 1H)2.19-2.31 (m, 1H) 3.13-3.22 (m, 1H) 3.40-3.49 (m, 1H) 3.49-3.64 (m, 1H)4.29-4.39 (m, 3H) 4.45 (s, 1H) 6.78 (d, J = 8.80 Hz, 1H) 7.21 (t, J =6.75 Hz, 1H) 7.47-7.60 (m, 1H) 7.70 (d, J = 7.82 Hz, 1H) 7.91 (d, J =2.35 Hz, 1H) 7.96 (d, J = 2.35 Hz, 1H) 8.03 (d, J = 8.80 Hz, 1H) 6.38

(400 MHz, DMSO-d₆) 1.11 (s, 5H) 1.73 (t, J = 7.04 Hz, 2H) 3.24 (s, 2H)3.59 (t, J = 6.85 Hz, 2H) 4.30-4.45 (m, 5H) 6.78 (d, J = 9.00 Hz, 1H)7.17-7.25 (m, 1H) 7.47-7.60 (m, 2H) 7.70 (d, J = 7.82 Hz, 1H) 7.90 (d, J= 2.74 Hz, 1H) 7.96 (d, J = 2.35 Hz, 1H) 8.03 (d, J = 8.61 Hz, 1H) 6.39

(400 MHz, DMSO-d₆) 1.62-1.74 (m, 1H) 2.02 (dd, J = 11.74, 5.09 Hz, 1H)3.25-3.32 (m, 4H) 3.37-3.43 (m, 2H) 3.46-3.59 (m, 3H) 4.30-4.46 (m, 5H)6.78 (d, J = 9.00 Hz, 1H) 7.16-7.24 (m, 1H) 7.48-7.60 (m, 2H) 7.70 (d, J= 7.82 Hz, 1H) 7.92 (d, J = 2.35 Hz, 1H) 7.97 (d, J = 2.74 Hz, 1H) 8.03(d, J = 9.00 Hz, 1H) 6.40

(300 MHz, MeOH) 8.22 (1H, d, J = 2.6 Hz), 8.15 (1H, d, J = 2.5 Hz), 8.01(1H, d, J = 8.9 Hz), 7.64-7.74 (2H, m), 7.55 (1H, td, J = 7.7, 1.4 Hz),7.18-7.30 (1H, m), 6.77 (1H, d, J = 8.9 Hz), 4.54-4.67 (2H, m), 4.38-4.49 (3H, m), 3.57 (2H, d, J = 12.9 Hz), 2.76-3.03 (2H, m), 2.42 (1H,m), 1.96-2.13 (2H, m), 1.66-1.96 (2H, m). 6.41

(300 MHz, MeOH) 8.22 (1H, d, J = 2.6 Hz), 8.15 (1H, d, J = 2.5 Hz), 8.01(1H, d, J = 8.9 Hz), 7.64-7.74 (2H, m), 7.55 (1H, td, J = 7.7, 1.4 Hz),7.18-7.30 (1H, m), 6.77 (1H, d, J = 8.9 Hz), 4.54-4.67 (2H, m),4.38-4.49 (3H, m), 3.31-3-36 (2H, m), 3.00-3.16 (3H, m), 1.99-2.22 (4H,m) 6.42

(300 MHz, MeOH) 8.22 (1H, d, J = 2.6 Hz), 8.15 (1H, d, J = 2.5 Hz), 8.01(1H, d, J = 8.9 Hz), 7.64-7.74 (2H, m), 7.55 (1H, td, J = 7.7, 1.4 Hz),7.18-7.30 (1H, m), 6.77 (1H, d, J = 8.9 Hz), 4.54-4.67 (2H, m),4.38-4.49 (3H, m), 3.31-3-36 (4H, m), 2.13-2.27 (4H, m) 6.43

(300 MHz, MeOH) 8.22 (1H, d, J = 2.6 Hz), 8.15 (1H, d, J = 2.5 Hz), 8.01(1H, d, J = 8.9 Hz), 7.64-7.74 (2H, m), 7.55 (1H, td, J = 7.7, 1.4 Hz),7.18-7.30 (1H, m), 6.77 (1H, d, J = 8.9 Hz), 4.54-4.67 (2H, m),4.38-4.49 (3H, m), 3.83-3.99 (4H, m), 3.06-3.27 (4H, m) 6.44

(300 MHz, MeOH) 8.20 (1H, d, J = 2.5 Hz), 8.14 (1H, d, J = 2.6 Hz), 8.01(1H, d, J = 8.9 Hz), 7.64-7.74 (2H, m), 7.49-7.60 (1H, m), 7.20-7.30(1H, m), 6.77 (1H, d, J = 8.9 Hz), 4.94 (1H, dt, J = 6.6, 3.3 Hz), 4.78(1H, dt, J = 6.7, 3.3 Hz), 4.54-4.67 (2H, m), 4.35-4.52 (3H, m),3.24-3.45 (1H, m), 3.05-3.22 (2H, m), 1.90-2.25 (4H, m) 6.45

(300 MHz, MeOH) 7.93-8.04 (3H, m), 7.64-7.73 (2H, m), 7.55 (1H, ddd, J =8.4, 7.0, 1.4 Hz), 7.19-7.30 (1H, m), 6.76 (1H, d, J = 8.9 Hz),4.45-4.57 (4H, m), 4.30-4.44 (3H, m), 4.10-4.26 (1H, m), 3.93-4.08 (2H,m), 3.38 (3H, s) 6.46

(300 MHz, MeOH) 8.09 (2H, q, J = 2.6 Hz), 8.01 (1H, d, J = 8.9 Hz),7.64-7.73 (2H, m), 7.55 (1H, ddd, J = 8.5, 6.9, 1.4 Hz), 7.25 (1H, td, J= 7.5, 1.0 Hz), 6.77 (1H, d, J = 9.1 Hz), 4.45-4.61 (8H, m), 4.10-4.27(1H, m) 6.47

(300 MHz, MeOH) 8.17 (1H, d, J = 2.5 Hz), 8.12 (1H, d, J = 2.6 Hz), 8.01(1H, d, J = 8.9 Hz), 7.69 (2H, dd, J = 8.0, 5.2 Hz), 7.55 (1H, td, J =7.7, 1.5 Hz), 7.20-7.30 (1H, m), 6.77 (1H, d, J = 8.9 Hz), 4.51-4.65(2H, m), 4.36-4.49 (3H, m), 3.09-3.38 (4H, m), 1.69-1.93 (4H, m), 1.32(3H, s) 6.48

(300 MHz, MeOH) 9.08-9.13 (1H, m), 8.77 (1H, d, J = 2.5 Hz), 8.50 (1H,d, J = 2.3 Hz), 8.28 (1H, s), 8.01 (1H, d, J = 9.1 Hz), 7.63-7.72 (2H,m), 7.50-7.59 (1H, m), 7.24 (1H, td, J = 7.5, 1.0 Hz), 6.75 (1H, d, J =8.9 Hz), 4.74 (1H, quin, J = 7.2 Hz), 4.46-4.60 (4H, m) 6.49

(300 MHz, MeOH) 8.60 (1H, d, J = 2.5 Hz), 8.40 (1H, d, J = 2.5 Hz), 8.24(1H, s), 7.99 (1H, d, J = 8.9 Hz), 7.62-7.74 (3H, m), 7.54 (1H, ddd, J =8.5, 7.0, 1.5 Hz), 7.23 (1H, td, J = 7.5, 1.0 Hz), 6.73 (1H, d, J = 9.1Hz), 4.74-4.84 (1H, m), 4.38-4.59 (4H, m), 2.22 (3H, s) 6.50

(300 MHz, DMSO-d₆) 8.03 (2H, dd, J = 5.7, 3.1 Hz), 7.96 (1H, d, J = 2.6Hz), 7.71 (1H, d, J = 7.6 Hz), 7.46-7.62 (3H, m), 7.21 (1H, ddd, J =8.0, 6.5, 1.6 Hz), 6.78 (1H, d, J = 8.8 Hz), 4.25-4.52 (7H, m),3.97-4.18 (1H, m), 3.92 (2H, dd, J = 8.1, 5.6 Hz), 1.40 (9H, s) 6.51

(300 MHz, DMSO-d₆) 8.25 (1H, d, J = 2.5 Hz), 8.20 (1H, d, J = 2.5 Hz),8.04 (1H, d, J = 8.9 Hz), 7.71 (1H, d, J = 8.2 Hz), 7.48-7.63 (2H, m),7.14-7.28 (1H, m), 6.80 (1H, d, J = 8.9 Hz), 4.44-4.56 (2H, m),4.23-4.44 (3H, m), 3.78-3.89 (2H, m), 2.99-3.12 (2H, m), 2.89 (2H, s),1.30 (6H, s) 6.52

(300 MHz, DMSO-d₆) 8.76 (1H, d, J = 2.5 Hz), 8.56 (1H, d, J = 2.5 Hz),7.96-8.07 (2H, m), 7.71 (1H, d, J = 7.6 Hz), 7.46-7.60 (2H, m), 7.35(1H, s), 7.22 (1H, ddd, J = 7.9, 6.5, 1.5 Hz), 6.76 (1H, d, J = 8.9 Hz),4.35-4.51 (2H, m), 4.24-4.31 (3H, m), 2.20 (3H, s). 6.53

(400 MHz, MeOH) 9.03 (1H, s), 8.12 (1H, d, J = 2.5 Hz), 8.05 (1H, d, J =2.5 Hz), 7.73 (1H, d, J = 7.6 Hz), 7.60-7.69 (1H, m), 7.51 (1H, d, J =8.6 Hz), 7.21 (1H, t, J = 7.5 Hz), 4.50-4.58 (2H, m), 4.24-4.42 (3H, m),3.22-3.32 (2H, m), 2.86-3.06 (3H, m), 2.00-2.12 (2H, m), 1.87-2.00 (2H,m) 6.54

(400 MHz, MeOH) 8.52 (1H, d, J = 2.3 Hz), 8.32 (2H, s), 7.88 (1H, d, J =8.8 Hz), 7.75 (1H, s), 7.56 (2H, dd, J = 7.8, 4.1 Hz), 7.43 (1H, t, J =7.7 Hz), 7.12 (1H, t, J = 7.5 Hz), 6.63 (1H, d, J = 9.0 Hz), 4.65-4.73(1H, m), 4.54 (2H, s), 4.33-4.46 (4H, m) 6.55

(300 MHz, DMSO-d₆) 8.78 (2H, d, J = 2.5 Hz), 8.57 (2H, d, J = 2.3 Hz),8.03 (3H, dd, J = 5.1, 3.8 Hz), 7.71 (2H, d, J = 7.6 Hz), 7.43-7.62 (5H,m), 7.22 (2H, ddd, J = 7.9, 6.6, 1.5 Hz), 6.76 (2H, d, J = 8.9 Hz), 5.06(2H, t, J = 5.6 Hz), 4.48 (2H, m), 4.28-4.31 (3H, m), 4.26 (2H, d, J =5.6 Hz). 6.56

(400 MHz, MeOH) 8.17 (1H, d, J = 2.5 Hz), 8.07 (1H, d, J = 2.5 Hz), 7.90(1H, d, J = 8.8 Hz), 7.57 (2H, dd, J = 8.0, 3.7 Hz), 7.40-7.48 (1H, m),7.13 (1H, t, J = 7.1 Hz), 6.66 (1H, d, J = 8.8 Hz), 4.41-4.56 (2H, m),4.28-4.41 (3H, m), 3.81 (2H, s), 3.41 (4H, s), 2.92 (3H, s) 6.57

(400 MHz, MeOH) 8.11 (1H, d, J = 2.5 Hz), 8.05 (1H, d, J = 2.5 Hz), 7.91(1H, d, J = 9.0 Hz), 7.58 (2H, dd, J = 7.7, 4.4 Hz), 7.40-7.47 (1H, m),7.14 (1H, t, J = 7.5 Hz), 6.99 (3H, s), 6.66 (1H, d, J = 9.0 Hz),4.43-4.57 (2H, m), 4.27-4.43 (3H, m), 3.58 (1H, d, J = 11.0 Hz), 3.35(1H, d, J = 12.7 Hz), 3.05-3.15 (1H, m), 2.77-2.96 (2H, m), 2.02-2.31(7H, m), 1.70-1.94 (3H, m) 6.58

(400 MHz, MeOH) 8.21 (1H, d, J = 2.5 Hz), 8.13 (1H, d, J = 2.5 Hz), 8.02(1H, d, J = 8.8 Hz), 7.69 (2H, dd, J = 7.6, 4.9 Hz), 7.56 (1H, t, J =7.6 Hz), 7.25 (1H, t, J = 7.4 Hz), 6.77 (1H, d, J = 8.8 Hz), 4.56-4.73(2H, m), 4.36-4.52 (3H, m), 3.69-3.83 (1H, m), 3.39 (1H, m), 2.97 (1H,t, J = 8.9 Hz), 2.76 (1H, dd, J = 12.1, 8.6 Hz), 1.91-2.02 (2H, m), 1.82(1H, m), 1.40-1.59 (10H, m), 1.29-1.40 (1H, m) 6.59

(300 MHz, MeOH) 8.56 (1H, d, J = 2.5 Hz), 8.44 (1H, d, J = 2.5 Hz), 7.69(2H, dd, J = 7.7, 5.6 Hz), 7.56 (1H, t, J = 7.7 Hz), 7.25 (1H, t, J =7.5 Hz), 6.78 (1H, d, J = 8.8 Hz), 4.54-4.72 (2H, m), 4.34-4.54 (3H, m),3.64 (2H, s), 3.09-3.28 (4H, m), 1.68-1.86 (4H, m), 1.31 (1H, m),0.84-1.01 (1H, m), 0.77 (1H, t, J = 6.8 Hz), 0.38-0.59 (2H, m),0.07-0.19 (2H, m) 6.60

(400 MHz, DMSO-d₆) 1.61-1.78 (m, 1H) 1.89 (br. s., 1H) 2.18 (s, 2H)2.98-3.16 (m, 3H) 3.20 (d, J = 11.15 Hz, 1H) 3.36-3.55 (m, 1H) 3.67 (d,J = 13.30 Hz, 1H) 4.06 (t, J = 11.05 Hz, 1H) 4.33 (d, J = 11.74 Hz, 1H)6.58 (d, J = 9.39 Hz, 1H) 7.17 (t, J = 7.34 Hz, 1H) 7.37-7.44 (m, 1H)7.44-7.53 (m, 1H) 7.56 (d, J = 7.43 Hz, 1H) 8.21 (d, J = 2.54 Hz, 1H)8.24 (d, J = 2.54 Hz, 1H)

Examples 6.61 and 6.62 Separated Stereoisomers of Example 6.1

Note: the absolute stereochemistry of each separated isomer was notfurther determined.2-(3-(3-(3-(pyridin-3-yl)pyrrolidin-1-yl)pyrazin-2-yl)azetidin-1-yl)quinoline(SCHEME 6, Example 6.1) was chirally separated by using a Chiralpak ASH(150×4.6 mm i.d.), mobile phase 85% liquid CO₂/15% methanol containing0.2% DEA (Flow rate: 4 ml/min, column temp: 40° C., outlet pressure: 100Bar, wavelength: 248 nm)

Separated Isomer Example 6.61

ESI-MS (M+1): 409. PDE10 IC₅₀ (uM): 0.0115.

¹H NMR δ (ppm) (400 MHz, DMSO-d₆) δ ppm 2.00-2.16 (m, 1H) 2.31-2.44 (m,1H) 3.46-3.57 (m, 1H) 3.57-3.68 (m, 2H) 3.68-3.81 (m, 1H) 3.81-3.90 (m,1H) 4.30-4.52 (m, 4H) 6.79 (d, J=9.00 Hz, 1H) 7.21 (t, J=7.24 Hz, 1H)7.39 (dd, J=7.82, 4.69 Hz, 1H) 7.45-7.61 (m, 2H) 7.71 (d, J=8.02 Hz, 1H)7.82 (d, J=7.83 Hz, 1H) 7.94-8.08 (m, 3H) 8.49 (d, J=4.50 Hz, 1H) 8.61(s, 1H)

Separated Isomer Example 6.62

ESI-MS (M+1): 409. PDE10 IC₅₀ (uM): 0.0022.

¹H NMR δ (ppm) (400 MHz, DMSO-d₆) δ ppm 2.10 (quin, J=9.93 Hz, 1H)2.30-2.44 (m, 1H) 3.46-3.58 (m, 1H) 3.58-3.68 (m, 2H) 3.70-3.81 (m, 1H)3.86 (dd, J=9.59, 7.43 Hz, 1H) 4.30-4.51 (m, 5H) 6.79 (d, J=9.00 Hz, 1H)7.22 (t, J=6.75 Hz, 1H) 7.39 (dd, J=7.82, 4.69 Hz, 1H) 7.47-7.61 (m, 2H)7.71 (d, J=7.82 Hz, 1H) 7.82 (d, J=7.83 Hz, 1H) 7.95-8.07 (m, 3H) 8.49(d, J=3.52 Hz, 1H) 8.61 (d, J=1.76 Hz, 1H)

Example 7 METHYL(1-(3-(1-(QUINOLIN-2-YL)AZETIDIN-3-YL)PYRAZIN-2-YL)PYRROLIDIN-3-YL)CARBAMATE

Step 1. tert-Butyl(1-(3-(1-(quinolin-2-yl)azetidin-3-yl)pyrazin-2-yl)pyrrolidin-3-yl)carbamate:To a round bottomed flask was added2-(3-(3-chloropyrazin-2-yl)azetidin-1-yl)quinoline (1.0337 g, 3.48mmol), tert-butyl pyrrolidin-3-ylcarbamate (commercially available fromTCI, 1.298 g, 6.97 mmol), and triethylamine (commercially available fromAldrich, 0.971 ml, 6.97 mmol) in DMSO (11.61 ml) to stir at 110° C.overnight.

The reaction mixture was diluted with water and extracted with CH₂Cl₂.The organic extract was washed with water, saturated NaCl, dried overMgSO₄, filtered and concentrated in vacuo. The crude product wasadsorbed onto a plug of silica gel and chromatographed through a Biotage50 g SNAP HP-silica column, eluting with a gradient of 10% to 100% EtOAcin hexane, to provide tert-butyl(1-(3-(1-(quinolin-2-yl)azetidin-3-yl)pyrazin-2-yl)pyrrolidin-3-yl)carbamate(1.3145 g, 2.94 mmol, 85% yield). ¹H NMR (400 MHz, DMSO-d₆) δ ppm 1.41(s, 9H) 1.86 (dq, J=12.35, 6.32 Hz, 1H) 2.01-2.15 (m, 1H) 3.34 (d,J=4.89 Hz, 1H) 3.44-3.54 (m, 1H) 3.54-3.62 (m, 1H) 3.61-3.71 (m, 1H)4.08 (d, J=5.67 Hz, 1H) 4.27-4.45 (m, 3H) 6.78 (d, J=8.80 Hz, 1H)7.15-7.26 (m, 1H) 7.47-7.60 (m, 1H) 7.71 (d, J=7.82 Hz, 1H) 7.93 (d,J=2.54 Hz, 1H) 7.98 (d, J=2.35 Hz, 1H) 8.03 (d, J=8.80 Hz, 1 H) ESI(M+1) 447.0; calc for C₂₅H₃₀N₆O₂ 446.

STEP 2.1-(3-(1-(QUINOLIN-2-YL)AZETIDIN-3-YL)PYRAZIN-2-YL)PYRROLIDIN-3-AMINE

To a round bottomed flask was added tert-butyl(1-(3-(1-(quinolin-2-yl)azetidin-3-yl)pyrazin-2-yl)pyrrolidin-3-yl)carbamate(1.3145 g, 2.94 mmol) and hydrogen chloride, 1M in diethyl ether (0.089ml, 2.94 mmol) to stir. Solvent was evaporated. The reaction mixture wasdiluted with saturated sodium bicarbonate and extracted with CH₂Cl₂. Theorganic extract was washed with water, saturated Na₂CO₃, saturated NaCl,dried over MgSO₄, filtered and concentrated in vacuo to give1-(3-(1-(quinolin-2-yl)azetidin-3-yl)pyrazin-2-yl)pyrrolidin-3-amine(0.696 g, 2.009 mmol, 68.2% yield).

STEP 3. METHYL(1-(3-(1-(QUINOLIN-2-YL)AZETIDIN-3-YL)PYRAZIN-2-YL)PYRROLIDIN-3-YL)CARBAMATE

To a round bottomed flask was added1-(3-(1-(quinolin-2-yl)azetidin-3-yl)pyrazin-2-yl)pyrrolidin-3-amine(0.0974 g, 0.281 mmol), pyridine (commercially available throughAldrich, 0.045 ml, 0.562 mmol), and 4-(pyrrolidin-1-yl)pyridine (PPY)(commercially available through Alfa Aesar, 0.042 g, 0.281 mmol) to stirat RT in DCM (0.937 ml). Methyl carbonochloridate (commerciallyavailable through Aldrich, 0.027 ml, 0.422 mmol) was added and allowedto stir overnight. The crude product was adsorbed onto a plug of silicagel and chromatographed through a Biotage 50 g SNAP HP-silica column,eluting with a gradient of 1% to 6% MeOH in CH₂Cl₂, to provide methyl(1-(3-(1-(quinolin-2-yl)azetidin-3-yl)pyrazin-2-yl)pyrrolidin-3-yl)carbamate.

The following Table 19A lists compounds of Examples 7.1 to 7.5, whichwere made analogous to Scheme 7, Steps 2 and 3, by using the appropriatematerials and reaction conditions, which are listed in Table 19B. TheNMR data of the Examples are listed in Table 19C.

TABLE 19A EXAMPLES 7.1 TO 7.5 ESI-MS IC₅₀ Ex. # Structure Chemical Name(M + 1) (μM) 7.1

(R- & S-)-methyl (1-(3-(1- (quinolin-2-yl)azetidin-3-yl)pyrazin-2-yl)pyrrolidin-3- yl)carbamate 405.1 0.002 7.2

1-(3-(1-(quinolin-2-yl)azetidin- 3-yl)pyrazin-2-yl)pyrrolidin-3- amine347.1 0.038 7.3

(R- & S-)-N-(1-(3-(1- (quinolin-2-yl)azetidin-3-yl)pyrazin-2-yl)pyrrolidin-3- yl)methanesulfonamide 425 0.011 7.4

(R- & S-)-ethyl (1-(3-(1- (quinolin-2-yl)azetidin-3-yl)pyrazin-2-yl)pyrrolidin-3- yl)carbamate 419 0.001 7.5

(R- & S-)-2-methoxy-N-(1-(3- (1-(quinolin-2-yl)azetidin-3-yl)pyrazin-2-yl)pyrrolidin-3- yl)acetamide 419 0.0044

TABLE 19B STARTING MATERIALS AND REACTION CONDITION FOR PREPARATION OFEXAMPLES 7.3 TO 7.5. Examples 7.1 to 7.2 are prepared as described inScheme 7. Unless otherwise stated, all starting materials arecommercially available from common vendors Key Starting Purification Ex.# Material(s) Key Starting Material(s) Reaction Condition Condition* 7.3

4-PPY, Py, DCM, RT A 7.4

4-PPY, Py, DCM, RT A 7.5

4-PPY, Py, DCM, RT A *Purification Method A: purification by silica gelchromatography: (Biotage 50 g SNAP HP-silica column, eluting with agradient of 1% to 6% MeOH in CH₂Cl₂).

TABLE 19C 1H NMR δ (PPM) DATA FOR EXAMPLES 7.1 TO 7.5 Ex. # StructureNMR 7.1

(400 MHz, DMSO-d₆) 0.83-0.94 (m, 1H) 1.20-1.40 (m, 1H) 1.70 (dq, J =12.37, 6.31 Hz, 1H) 1.86 (br. s., 1H) 1.96-2.09 (m, 1H) 3.17 (dd, J =9.98, 4.69 Hz, 1H) 3.44-3.59 (m, 2H) 3.59-3.71 (m, 2H) 4.30-4.48 (m, 4H)6.80 (d, J = 9.00 Hz, 1H) 7.23 (t, J = 6.85 Hz, 1H) 7.48-7.62 (m, 2H)7.72 (d, J = 7.82 Hz, 1H) 7.92 (d, J = 2.35 Hz, 1H) 7.98 (d, J = 2.35Hz, 1H) 8.05 (d, J = 9.00 Hz, 1H) 7.2

(400 MHz, DMSO-d₆) 1.88 (dq, J = 12.52, 6.39 Hz, 1H) 2.04-2.17 (m, 3H)3.35 (dd, J = 10.56, 4.89 Hz, 1H) 3.47-3.65 (m, 4H) 3.68 (dd, J = 10.56,6.26 Hz, 1H) 4.07-4.17 (m, 1H) 4.29-4.44 (m, 4H) 6.78 (d, J = 8.80 Hz,1H) 7.16-7.25 (m, 1H) 7.45-7.59 (m, 2H) 7.70 (d, J = 7.63 Hz, 1H) 7.93(d, J = 2.35 Hz, 1H) 7.98 (d, J = 2.54 Hz, 1H) 8.03 (d, J = 9.00 Hz, 1H)7.3

(400 MHz, DMSO-d₆) 1.86-1.99 (m, 1H) 2.12-2.26 (m, 1H) 3.00 (s, 2H) 3.41(dd, J = 10.56, 5.67 Hz, 1H) 3.49-3.65 (m, 1H) 3.72 (dd, J = 10.37, 6.46Hz, 1H) 4.00 (br. s., 1H) 4.28-4.46 (m, 3H) 6.79 (d, J = 8.80 Hz, 1H)7.21 (t, J = 7.24 Hz, 1H) 7.42 (br. s., 1H) 7.46-7.61 (m, 1H) 7.71 (d, J= 8.02 Hz, 1H) 7.96 (d, J = 2.35 Hz, 1H) 8.00 (d, J = 2.54 Hz, 1H) 8.04(d, J = 8.80 Hz, 1H) 7.4

(400 MHz, DMSO-d₆) 1.19 (t, J = 7.04 Hz, 3H) 1.90 (dq, J = 12.57, 6.57Hz, 1H) 2.06-2.19 (m, 1H) 3.36 (dd, J = 10.56, 4.89 Hz, 1H) 3.48-3.57(m, 1H) 3.58-3.67 (m, 1H) 3.70 (dd, J = 10.47, 6.16 Hz, 1H) 4.03 (q, J =7.04 Hz, 2H) 4.08-4.20 (m, 1H) 4.32-4.52 (m, 4H) 6.85 (d, J = 8.61 Hz,1H) 7.27 (t, J = 7.04 Hz, 1H) 7.47 (d, J = 6.26 Hz, 1H) 7.53-7.67 (m,2H) 7.76 (d, J = 7.82 Hz, 1H) 7.96 (d, J = 2.54 Hz, 1H) 8.01 (d, J =2.54 Hz, 1H) 8.11 (d, J = 8.41 Hz, 1H) 7.5

(400 MHz, DMSO-d₆) 1.88-2.01 (m, 1H) 2.04-2.19 (m, 1H) 3.31 (s, 3H) 3.44(dd, J = 10.37, 5.48 Hz, 1H) 3.48-3.63 (m, 2H) 3.68 (dd, J = 10.27, 6.55Hz, 1H) 3.83 (s, 2H) 4.29- 4.44 (m, 5H) 6.78 (d, J = 9.00 Hz, 1H) 7.21(t, J = 7.34 Hz, 1H) 7.47-7.59 (m, 2H) 7.70 (d, J = 8.02 Hz, 1H) 7.94(d, J = 2.54 Hz, 1H) 7.99 (d, J = 2.54 Hz, 1H) 8.03 (d, J = 8.80 Hz, 2H)

Examples 8.1 and 8.2 Example 8.12-(3-(3-(1,4-DIAZEPAN-1-YL)PYRAZIN-2-YL)AZETIDIN-1-YL)QUINOLINE

To a round bottomed flask was added tert-butyl4-(3-(1-(quinolin-2-yl)azetidin-3-yl)pyrazin-2-yl)-1,4-diazepane-1-carboxylate(0.5340 g, 1.159 mmol, SCHEME 6, Example 6.15) and HCl, (1.0 M solutionin diethyl ether (1.159 ml, 1.159 mmol)) and the reaction was allowed tostir at RT. After 1 h, the reaction mixture was concentrated, thendiluted with saturated Na₂CO₃ and extracted with CH₂Cl₂. The organicextract was washed with saturated Na₂CO₃, saturated NaCl, dried overMgSO₄, filtered and concentrated in vacuo to give2-(3-(3-(1,4-diazepan-1-yl)pyrazin-2-yl)azetidin-1-yl)quinoline (0.3627g, 1.006 mmol, 87% yield).

ESI-MS (M+1): 361.1. PDE10 IC₅₀ (μM): 0.050.

Example 8.2 METHYL4-(3-(1-(QUINOLIN-2-YL)AZETIDIN-3-YL)PYRAZIN-2-YL)-1,4-DIAZEPANE-1-CARBOXYLATE

To a round bottomed flask was added2-(3-(3-(1,4-diazepan-1-yl)pyrazin-2-yl)azetidin-1-yl)quinoline (0.0772g, 0.214 mmol), pyridine (commercially available through Aldrich, 0.035ml, 0.428 mmol), and 4-(pyrrolidin-1-yl)pyridine (commercially availablethrough Alfa Aesar, 0.032 g, 0.214 mmol) and the reaction was allowed tostir at RT in DCM (0.714 ml). Methyl carbonochloridate (commerciallyavailable through Aldrich, 0.021 ml, 0.321 mmol) was added and allowedto stir overnight. Upon completion, the solvent was evaporated. Thecrude product was adsorbed onto a plug of silica gel and chromatographedthrough a Biotage 50 g SNAP HP-silica column, eluting with a gradient of0.5% to 5% MeOH in CH₂CL₂, to provide methyl4-(3-(1-(quinolin-2-yl)azetidin-3-yl)pyrazin-2-yl)-1,4-diazepane-1-carboxylate(0.0632 g, 0.151 mmol, 70.5% yield). ESI-MS (M+1): 419.0. PDE10 IC₅₀(μM): 0.0046.

The following Table 20 lists NMR data of Examples 8.1 to 8.2, which weremade as described in the above Scheme 8.

TABLE 20 1H NMR δ (PPM) DATA FOR EXAMPLES 8.1 TO 8.2 Ex. # Structure NMR8.1

(400 MHz, DMSO-d₆) 1.86 (t, J = 5.58 Hz, 1 H) 2.85 (t, J = 5.77 Hz, 1 H)2.93-3.03 (m, 1 H) 3.41-3.53 (m, 2 H) 4.19-4.34 (m, 2 H) 4.38-4.47 (m, 2H) 6.79 (d, J = 8.80 Hz, 1 H) 7.21 (t, J = 7.34 Hz, 1 H) 7.46-7.61 (m, 1H) 7.71 (d, J = 7.82 Hz, 1 H) 8.03 (d, J = 2.54 Hz, 2 H) 8.2

(400 MHz, DMSO-d₆) 1.93 (br. s., 2 H) 3.42 (br. s., 2 H) 3.48 (br. s., 2H) 3.53 (d, J = 4.69 Hz, 2 H) 3.56-3.65 (m, 5 H) 4.21- 4.35 (m, 3 H)4.41-4.51 (m, 2 H) 6.81 (d, J = 9.00 Hz, 1 H) 7.19-7.27 (m, 1 H) 7.49-7.62 (m, 2 H) 7.73 (d, J = 7.82 Hz, 1 H) 8.05 (d, J = 8.80 Hz, 1 H) 8.11(dd, J = 12.52, 2.54 Hz, 2 H)

Example 9.1N-METHYL-METHYL(1-(3-(1-(QUINOLIN-2-YL)AZETIDIN-3-YL)PYRAZIN-2-YL)PYRROLIDIN-3-YL)CARBAMATESTEP 1.N-METHYL-1-(3-(1-(QUINOLIN-2-YL)AZETIDIN-3-YL)PYRAZIN-2-YL)PYRROLIDIN-3-AMINE

To a round bottomed flask was added tert-butylmethyl(1-(3-(1-(quinolin-2-yl)azetidin-3-yl)pyrazin-2-yl)pyrrolidin-3-yl)carbamate(3.0 g, 6.51 mmol) and hydrogen chloride, 5-6N in isopropanol (0.237 g,6.51 mmol) to stir overnight. Solvent was evaporated and the reactionmixture was diluted with water and extracted with EtOAc. The organicextract was washed with water, saturated Na₂CO₃, saturated NaCl, anddried over MgSO4, filtered and concentrated in vacuo to giveN-methyl-1-(3-(1-(quinolin-2-yl)azetidin-3-yl)pyrazin-2-yl)pyrrolidin-3-amine(1.0339 g, 2.87 mmol, 44.0% yield). ¹H NMR (400 MHz, DMSO-d₆) δ ppm1.71-1.83 (m, 1H) 2.02 (dt, J=12.18, 5.94 Hz, 1H) 2.32 (s, 2H) 3.16-3.28(m, 1H) 3.32 (br. s., 1H) 3.42-3.52 (m, 1H) 3.54-3.67 (m, 1H) 4.29-4.45(m, 4H) 6.78 (d, J=8.80 Hz, 1H) 7.17-7.25 (m, 1H) 7.48-7.59 (m, 2H) 7.71(d, J=7.83 Hz, 1H) 7.91 (d, J=2.54 Hz, 1H) 7.97 (d, J=2.35 Hz, 1H) 8.03(d, J=8.80 Hz, 1H)

STEP 2.N-METHYL-METHYL(1-(3-(1-(QUINOLIN-2-YL)AZETIDIN-3-YL)PYRAZIN-2-YL)PYRROLIDIN-3-YL)CARBAMATE

14 Mar. 2011 To a round bottomed flask was addedN-methyl-1-(3-(1-(quinolin-2-yl)azetidin-3-yl)pyrazin-2-yl)pyrrolidin-3-amine(0.0999 g, 0.277 mmol), pyridine (0.045 ml, 0.554 mmol), and4-(pyrrolidin-1-yl)pyridine (0.041 g, 0.277 mmol) to stir at RT in DCM(0.924 ml). Methyl carbonochloridate (0.027 ml, 0.416 mmol) was addedand allowed to stir for 2 h. Solvent was evaporated and the crudeproduct was adsorbed onto a plug of silica gel and chromatographedthrough a Biotage 50 g SNAP HP-silica column, eluting with a gradient of1% to 4% MeOH in CH₂Cl₂, to provide methylmethyl(1-(3-(1-(quinolin-2-yl)azetidin-3-yl)pyrazin-2-yl)pyrrolidin-3-yl)carbamate(0.0307 g, 0.073 mmol, 26.5% yield).

The following Table 21A lists compounds of Examples 9.1 to 9.3, whichwere made analogous to Scheme 9 by using the appropriate materials andreaction conditions, which are listed in Table 21B. The NMR data of theExamples are listed in Table 21C.

TABLE 21A EXAMPLES 9.1 TO 9.3 ESI-MS IC₅₀ Ex. # Structure Chemical Name(M + 1) (uM) 9.1

N-methyl-methyl(1-(3-(1- (quinolin-2-yl)azetidin-3-yl)pyrazin-2-yl)pyrrolidin-3- yl)carbamate 419.0 0.00052 9.2

N-methyl-N-(1-(3-(1-(quinolin- 2-yl)azetidin-3-yl)pyrazin-2-yl)pyrrolidin-3- yl)methanesulfonamide 439.0 0.00568 9.3

Ethyl methyl(1-(3-(1-(quinolin- 2-yl)azetidin-3-yl)pyrazin-2-yl)pyrrolidin-3-yl)carbamate 433.1 0.002

TABLE 21B STARTING MATERIALS AND REACTION CONDITION FOR PREPARATION OFEXAMPLES 9.1 TO 9.3. Unless otherwise stated, all starting materials arecommercially available from common vendors. Reaction Purification Ex. #Starting Material 1 Starting Material 2 Condition Condition* 9.1

4-PPY, Py, DCM A 9.2

4-PPY, Py, DCM A 9.3

4-PPY, Py, DCM A *Purification condition: Method A: flash columnchromatography on silica gel using Biotage 50 g SNAP HP-silica column,eluting with a gradient of 1% to 4% MeOH in CH₂Cl₂

TABLE 21C 1H NMR δ (PPM) DATA FOR EXAMPLES 9.1 TO 9.3 Ex. # StructureNMR 9.1

(400 MHz, DMSO-d₆) 2.09 (q, J = 6.91 Hz, 2 H) 2.86 (s, 3 H) 3.49-3.61(m, 4 H) 3.64 (s, 3 H) 4.31-4.41 (m, 4 H) 4.41-4.51 (m, 1 H) 6.79 (d, J= 8.80 Hz, 1 H) 7.22 (t, J = 6.85 Hz, 1 H) 7.48-7.60 (m, 2 H) 7.71 (d, J= 7.82 Hz, 1 H) 7.96-8.07 (m, 3 H) 9.2

(400 MHz, DMSO-d₆) 2.03-2.20 (m, 1 H) 2.83 (s, 2 H) 2.99 (s, 2 H)3.49-3.61 (m, 2 H) 4.31-4.51 (m, 3 H) 6.79 (d, J = 9.00 Hz, 1 H) 7.21(t, J = 6.85 Hz, 1 H) 7.46- 7.60 (m, 1 H) 7.71 (d, J = 7.82 Hz, 1 H)7.96-8.06 (m, 2 H) 9.3

(400 MHz, DMSO-d₆) 1.21 (t, J = 7.14 Hz, 2 H) 2.08 (q, J = 7.50 Hz, 1 H)2.85 (s, 2 H) 3.48-3.61 (m, 2 H) 4.08 (q, J = 7.04 Hz, 1 H) 4.29-4.40(m, 2 H) 4.40-4.49 (m, 1 H) 4.72 (br. s., 1 H) 6.79 (d, J = 9.00 Hz, 1H) 7.21 (t, J = 7.24 Hz, 1 H) 7.47-7.60 (m, 1 H) 7.70 (d, J = 7.82 Hz, 1H) 7.95-8.06 (m, 2 H)

Example 10.12-(3-(3-(4-CHLOROPHENYL)PYRAZIN-2-YL)AZETIDIN-1-YL)QUINAZOLINE

2M aqueous sodium carbonate (0.378 mL, 0.756 mmol, J. T. Baker) wasadded to a stirred mixture of2-(3-(3-chloropyrazin-2-yl)azetidin-1-yl)quinazoline (0.075 g, 0.252mmol, Preparation 1), trans-dichlorobis(triphenylphosphine)palladium(ii) (0.009 g, 0.013 mmol, Strem), and 4-chlorophenylboronic acid (0.047g, 0.302 mmol, ASDI) in 1,4-dioxane (1 mL) in a sealed tube under anargon atmosphere. The reaction mixture was stirred at 80° C. for 17 h.The reaction mixture was concentrated in vacuo and diluted with DCM. Theresulting suspension was filtered, and the filtrate was concentrated invacuo. The resulting crude material was purified via reverse phase HPLC(Column: Xbridge 19×100 mm, 5 μm, 1771302301) eluting with 0.1% NH₄OH inacetonitrile/water to give 0.060 g (64%) of a yellow amorphous solid.

¹H NMR (500 MHz, DMSO-d₆) δ ppm 4.28-4.38 (m, 5H) 7.25-7.30 (m, 1H) 7.52(d, J=8.48 Hz, 1H) 7.62 (s, 4H) 7.70-7.75 (m, 1H) 7.84 (br. d, J=7.80Hz, 1H) 8.64 (d, J=2.41 Hz, 1H) 8.70 (d, J=2.41 Hz, 1H) 9.18 (s, 1H).ESI (M+1) 374.0; calc for C₂₁H₁₆ClN₅ 373.

The following Table 22A lists compounds of Examples 10.1 to 10.20, whichwere made analogous to Scheme 10 by using the appropriate materials andreaction conditions, which are listed in Table 22B. The NMR data of theExamples are listed in Table 22C.

TABLE 22A EXAMPLES 10.1 TO 10.20 ESI-MS Ex. # Structure Chemical Name(M + 1) IC₅₀ (μM) 10.1

2-(3-(3-(4- chlorophenyl)pyrazin-2- yl)azetidin-1-yl)quinazoline 374.00.00482 10.2

2-(3-(3-(3- chlorophenyl)pyrazin-2- yl)azetidin-1-yl)quinazoline 374.00.00615 10.3

2-(3-(3-(2- chlorophenyl)pyrazin-2- yl)azetidin-1-yl)quinazoline 374.00.0309 10.4

2-(3-(3-(o-tolyl)pyrazin-2- yl)azetidin-1-yl)quinazoline 354.2 0.017810.5

1-(4-(3-(1-(quinazolin-2- yl)azetidin-3-yl)pyrazin-2- yl)phenyl)ethanone382.2 0.00738 10.6

1-(3-(3-(1-(quinazolin-2- yl)azetidin-3-yl)pyrazin-2- yl)phenyl)ethanone382.2 0.00136 10.7

N-(3-(3-(1-(quinazolin-2- yl)azetidin-3-yl)pyrazin-2-yl)phenyl)acetamide 397.2 0.000635 10.8

N-(4-(3-(1-(quinazolin-2- yl)azetidin-3-yl)pyrazin-2-yl)phenyl)methanesulfonamide 433.2 0.00336 10.9

N-(3-(3-(1-(quinazolin-2- yl)azetidin-3-yl)pyrazin-2-yl)phenyl)methanesulfonamide 433.2 0.00959 10.10

2-(3-(3-(1H-indol-6-yl)pyrazin- 2-yl)azetidin-1-yl)quinazoline 379.20.00525 10.11

2-(3-(3-(1-methyl-1H-indol-5- yl)pyrazin-2-yl)azetidin-1- yl)quinazoline393.2 0.00595 10.12

2-(3-(3-(1-methyl-1H-indol-6- yl)pyrazin-2-yl)azetidin-1- yl)quinazoline393.2 0.00298 10.13

5-(3-(1-(quinazolin-2- yl)azetidin-3-yl)pyrazin-2- yl)indolin-2-one395.2 0.00946 10.14

1-methyl-5-(3-(1-(quinazolin-2- yl)azetidin-3-yl)pyrazin-2-yl)indolin-2-one 409.2 0.018 10.15

1-methyl-6-(3-(1-(quinazolin-2- yl)azetidin-3-yl)pyrazin-2-yl)-1H-benzo[d]imidazol-2(3H)- one 410.2 0.0042 10.16

2-fluoro-4-(3-(1-(quinazolin-2- yl)azetidin-3-yl)pyrazin-2- yl)aniline373.1 0.00682 10.17

2-(3-(3-(p-tolyl)pyrazin-2- yl)azetidin-1-yl)quinazoline 354.2 0.0070810.18

2-methyl-6-(3-(1-(quinazolin-2- yl)azetidin-3-yl)pyrazin-2-yl)isoquinolin-1(2H)-one 421.1 0.01739 10.19

2-(3-(3-(1H-indazol-5- yl)pyrazin-2-yl)azetidin-1- yl)quinazoline 380.10.01216 10.20

5-(3-(1-(quinazolin-2- yl)azetidin-3-yl)pyrazin-2- yl)benzo[d]thiazole397.1 0.0044

TABLE 22B STARTING MATERIALS AND REACTION CONDITION FOR PREPARATION OFEXAMPLES 10.1 TO 10.20. Unless otherwise stated, all starting materialsare commercially available from common vendors. Reaction PurificationEx. # Key Starting Material(s) Key Starting Material(s) ConditionMethod* 10.1

Dioxane/water, 80° C., 17 h A 10.2

Dioxane/water, 80° C., 17 h A 10.3

Dioxane/water, 80° C., 17 h A 10.4

Dioxane/water, 80° C., 17 h A 10.5

Dioxane/water, 80° C., 17 h A 10.6

Dioxane/water, 80° C., 17 h A 10.7

Dioxane/water, 80° C., 17 h A 10.8

Dioxane/water, 80° C., 17 h A 10.9

Dioxane/water, 80° C., 17 h A 10.10

Dioxane/water, 80° C., 17 h A 10.11

Dioxane/water, 80° C., 17 h A 10.12

Dioxane/water, 80° C., 15 h A 10.13

Dioxane/water, 80° C., 15 h A 10.14

Dioxane/water, 80° C., 15 h A 10.15

Dioxane/water, 80° C., 15 h A 10.16

Pd₂Cl₂(PPh₃)₂, Na₂CO₃, (4 equiv), Dioxane/water, 80° C., 17 h B 10.17

Pd₂Cl₂(PPh₃)₂, Na₂CO₃, Dioxane/water, 80° C., 17 h B 10.18

Pd₂Cl₂(PPh₃)₂, Na₂CO₃, Dioxane/water, 80° C., 17 h B 10.19

Pd₂Cl₂(PPh₃)₂, Na₂CO₃, Dioxane/water, 80° C., 17 h B 10.20

Pd₂Cl₂(PPh₃)₂, Na₂CO₃, Dioxane/water, 80° C., 17 h A, B *PurificationMethods: Method A—reverse phase HPLC (Column: Xbridge 19x100 mm, 5 μm,1771302301) eluting with 0.1% NH₄OH in acetonitrile/water. MethodB—silica gel flash column chromatography eluting with 0% to 75% EtOAc inhexanes

TABLE 22C 1H NMR δ (PPM) DATA FOR EXAMPLES 10.1 TO 10.20 Ex. # StructureNMR 10.1

(500 MHz, DMSO-d₆) 4.28-4.38 (m, 5 H) 7.25-7.30 (m, 1 H) 7.52 (d, J =8.48 Hz, 1 H) 7.62 (s, 4 H) 7.70-7.75 (m, 1 H) 7.84 (br. d, J = 7.80 Hz,1 H) 8.64 (d, J = 2.41 Hz, 1 H) 8.70 (d, J = 2.41 Hz, 1 H) 9.18 (s, 1 H)10.2

(500 MHz, DMSO-d₆) 4.28-4.40 (m, 5 H) 7.28 (t, J = 7.40 Hz, 1 H)7.50-7.62 (m, 4 H) 7.66 (s, 1 H) 7.70-7.75 (m, 1 H) 7.84 (d, J = 7.79Hz, 1 H) 8.64 (d, J = 2.40 Hz, 1 H) 8.71 (d, J = 2.40 Hz, 1 H) 9.18 (s,1 H) 10.3

(500 MHz, DMSO-d₆) 3.96 (quin, J = 7.30 Hz, 1 H) 4.33 (m, 4 H) 7.28 (t,J = 7.39 Hz, 1 H) 7.50-7.59 (m, 4 H) 7.66 (br. d, J = 7.45 Hz, 1 H)7.70-7.75 (m, 1 H) 7.84 (d, J = 7.56 Hz, 1 H) 8.67 (d, J = 2.41 Hz, 1 H)8.76 (d, J = 2.52 Hz, 1 H) 9.18 (s, 1 H) 10.4

(500 MHz, DMSO-d₆) 2.07 (s, 3 H) 3.94- 4.01 (m, 1 H) 4.22 (t, J = 8.36Hz, 2 H) 4.28- 4.33 (m, 2 H) 7.23-7.30 (m, 2 H) 7.32-7.37 (m, 1 H)7.37-7.44 (m, 2 H) 7.51 (d, J = 8.48 Hz, 1 H) 7.70-7.74 (m, 1 H) 7.84(d, J = 7.56 Hz, 1 H) 8.63 (d, J = 2.52 Hz, 1 H) 8.70 (d, J = 2.41 Hz, 1H) 9.17 (s, 1 H) 10.5

(500 MHz, DMSO-d₆) 2.67 (s, 3 H) 4.29- 4.39 (m, 5 H) 7.28 (br. t, J =7.40, 7.40 Hz, 1 H) 7.51 (d, J = 8.25 Hz, 1 H) 7.71-7.77 (m, 3 H) 7.85(br. d, J = 8.00 Hz, 1 H) 8.13 (d, J = 8.36 Hz, 2 H) 8.68 (d, J = 2.41Hz, 1 H) 8.73 (d, J = 2.41 Hz, 1 H) 9.18 (s, 1 H) 10.6

(500 MHz, DMSO-d₆) 2.67 (s, 3 H) 4.30- 4.40 (m, 5 H) 7.27 (t, J = 7.39Hz, 1 H) 7.51 (d, J = 8.48 Hz, 1 H) 7.71 (t, J = 7.68 Hz, 2 H) 7.83 (d,J = 8.02 Hz, 1 H) 7.86 (d, J = 7.68 Hz, 1 H) 8.10 (d, J = 7.79 Hz, 1 H)8.13 (s, 1 H) 8.66 (d, J = 2.29 Hz, 1 H) 8.72 (d, J = 2.29 Hz, 1 H) 9.17(s, 1 H) 10.7

(500 MHz, DMSO-d₆) 2.09 (s, 3 H) 4.29- 4.45 (m, 5 H) 7.26-7.30 (m, 2 H)7.48 (t, J = 7.85 Hz, 1 H) 7.53 (d, J = 8.48 Hz, 1 H) 7.67 (br. d, J =8.00 Hz, 1 H) 7.71-7.75 (m, 1 H) 7.83-7.87 (m, 2 H) 8.63 (d, J = 2.41Hz, 1 H) 8.68 (d, J = 2.41 Hz, 1 H) 9.19 (s, 1 H) 10.13 (s, 1 H) 10.8

(500 MHz, DMSO-d₆) 3.10 (s, 3 H) 4.27- 4.32 (m, 2 H) 4.36-4.42 (m, 3 H)7.28 (br. t, J = 7.40, 7.40 Hz, 1 H) 7.38 (d, J = 8.59 Hz, 2 H) 7.52 (d,J = 8.48 Hz, 1 H) 7.57 (d, J = 8.59 Hz, 2 H) 7.71-7.75 (m, 1 H) 7.85(br. d, J = 8.00 Hz, 1 H) 8.61 (d, J = 2.40 Hz, 1 H) 8.65 (d, J = 2.41Hz, 1 H) 9.18 (s, 1 H) 10.05 (s, 1 H) 10.9

(500 MHz, DMSO-d₆) 3.07 (s, 3 H) 4.30- 4.37 (m, 3 H) 4.38-4.44 (m, 2 H)7.29 (br. t, J = 7.50, 7.50 Hz, 1 H) 7.33-7.39 (m, 3 H) 7.51-7.55 (m, 2H) 7.71-7.75 (m, 1 H) 7.86 (br. d, J = 8.10 Hz, 1 H) 8.64 (d, J = 2.41Hz, 1 H) 8.70 (d, J = 2.41 Hz, 1 H) 9.19 (s, 1 H) 9.97 (s, 1 H) 10.10

(500 MHz, DMSO-d₆) 4.30-4.40 (m, 4 H) 4.42-4.49 (m, 1 H) 6.52-6.54 (m, 1H) 7.24 (dd, J = 8.25, 1.49 Hz, 1 H) 7.27 (m, J = 7.80, 7.80 Hz, 1 H)7.49 (t, J = 2.75 Hz, 1 H) 7.51 (d, J = 8.48 Hz, 1 H) 7.61 (s, 1 H)7.68-7.74 (m, 2 H) 7.82-7.86 (m, 1 H) 8.62 (d, J = 2.40 Hz, 1 H) 8.63(d, J = 2.40 Hz, 1 H) 9.17 (s, 1 H) 11.30 (br. s., 1 H) 10.11

(500 MHz, DMSO-d₆) 3.87 (s, 3 H) 4.25- 4.36 (m, 4 H) 4.45-4.52 (m, 1 H)6.57 (d, J = 2.86 Hz, 1 H) 7.27 (br. t, J = 7.40, 7.40 Hz, 1 H) 7.39(dd, J = 8.42, 1.55 Hz, 1 H) 7.44 (d, J = 2.98 Hz, 1 H) 7.50 (d, J =8.59 Hz, 1 H) 7.60 (d, J = 8.48 Hz, 1 H) 7.69-7.73 (m, 1 H) 7.77 (d, J =1.26 Hz, 1 H) 7.83 (br. d, J = 7.10 Hz, 1 H) 8.60-8.63 (m, 2H) 9.16 (s,1 H) 10.12

(500 MHz, DMSO-d₆) 3.88 (s, 3 H) 4.28- 4.38 (m, 4 H) 4.47-4.54 (m, 1 H)6.53 (d, J = 2.86 Hz, 1 H) 7.24-7.29 (m, 2 H) 7.47 (d, J = 3.09 Hz, 1 H)7.51 (d, J = 8.48 Hz, 1 H) 7.64 (s, 1 H) 7.70 (m, J = 8.40 Hz, 2 H) 7.83(br. d, J = 7.80 Hz, 1 H) 8.63 (d, J = 2.40 Hz, 1 H) 8.65 (d, J = 2.40Hz, 1 H) 9.16 (s, 1 H) 10.13

(500 MHz, DMSO-d₆) 3.60 (s, 2 H) 4.26- 4.31 (m, 2 H) 4.36-4.45 (m, 3 H)6.98 (d, J = 8.02 Hz, 1 H) 7.26-7.30 (m, 1 H) 7.41 (d, J = 8.02 Hz, 1 H)7.44 (s, 1 H) 7.51 (d, J = 8.48 Hz, 1 H) 7.70-7.75 (m, 1 H) 7.85 (br. d,J = 7.20 Hz, 1 H) 8.59 (d, J = 2.29 Hz, 1 H) 8.62 (d, J = 2.41 Hz, 1 H)9.18 (s, 1 H) 10.57 (s, 1 H) 10.14

(500 MHz, DMSO-d₆) 3.20 (s, 3 H) 3.68 (s, 2 H) 4.27-4.32 (m, 2 H)4.35-4.41 (m, 2 H) 4.41-4.48 (m, 1 H) 7.14 (d, J = 7.90 Hz, 1 H) 7.28(br. t, J = 7.50, 7.50 Hz, 1 H) 7.49-7.53 (m, 3 H) 7.70-7.75 (m, 1 H)7.85 (br. d, J = 7.20 Hz, 1 H) 8.60 (d, J = 2.41 Hz, 1 H) 8.63 (d, J =2.41 Hz, 1 H) 9.18 (s, 1 H) 10.15

(500 MHz, DMSO-d₆) 3.35 (s, 3 H) 4.27- 4.32 (m, 2 H) 4.34-4.40 (m, 2 H)4.43-4.50 (m, 1 H) 7.14 (d, J = 7.90 Hz, 1 H) 7.21 (dd, J = 8.00, 1.50Hz, 1 H) 7.28 (t, J = 7.45 Hz, 1 H) 7.30 (s, 1 H) 7.51 (d, J = 8.48 Hz,1 H) 7.70- 7.74 (m, 1 H) 7.84 (br. d, J = 7.90 Hz, 1 H) 8.61 (d, J =2.41 Hz, 1 H) 8.64 (d, J = 2.40 Hz, 1 H) 9.18 (s, 1 H) 11.05 (s, 1 H)10.16

(500 MHz, d-CHLOROFORM) 3.98 (br. s., 2 H) 4.41 (quin, J = 7.20 Hz, 1 H)4.53 (d, J = 7.20 Hz, 4 H) 6.88 (t, J = 8.61 Hz, 1 H) 7.11 (br. d, J =8.00 Hz, 1 H) 7.20-7.27 (m, 2 H) 7.60- 7.70 (m, 3 H) 8.49 (d, J = 2.15Hz, 1 H) 8.52 (d, J = 2.15 Hz, 1 H) 9.02 (s, 1 H) 10.17

(500 MHz, d-CHLOROFORM) 2.45 (s, 3 H) 4.37 (quin, J = 7.20 Hz, 1 H)4.45-4.57 (m, 4 H) 7.23 (t, J = 7.34 Hz, 1 H) 7.32 (d, ¹H NMR (500 MHz,d-CHLOROFORM) δ J = 8.02 Hz, 2 H) 7.41 (d, J = 8.00 Hz, 2 H) 7.60-7.70(m, 3 H) 8.52 (d, J = 2.20 Hz, 1 H) 8.56 (d, J = 2.15 Hz, 1 H) 9.01 (s,1 H) 10.18

(500 MHz, d-CHLOROFORM) 3.66 (s, 3 H) 4.36 (quin, J = 7.40 Hz, 1 H)4.46-4.59 (m, 4 H) 6.55 (d, J = 7.43 Hz, 1 H) 7.16 (d, J = 7.43 Hz, 1 H)7.24 (t, J = 7.40 Hz, 1 H) 7.59-7.71 (m, 5 H) 8.56-8.60 (m, 2 H) 8.65(d, J = 2.15 Hz, 1 H) 9.01 (s, 1 H) 10.19

(500 MHz, d-CHLOROFORM) 4.40-4.59 (m, 5 H) 7.21-7.25 (m, 1 H) 7.54-7.70(m, 5 H) 7.90 (s, 1 H) 8.17 (s, 1 H) 8.56 (d, J = 2.30 Hz, 1 H) 8.60 (d,J = 2.35 Hz, 1 H) 9.01 (s, 1 H) 10.53 (br. s, 1 H) 10.20

(400 MHz, d-CHLOROFORM) 4.42-4.59 (m, 5 H) 7.23 (t, J = 7.43 Hz, 1 H)7.59-7.71 (m, 4 H) 8.13 (d, J = 8.41 Hz, 1 H) 8.29 (d, J = 0.78 Hz, 1 H)8.59 (d, J = 2.35 Hz, 1 H) 8.64 (d, J = 2.35 Hz, 1 H) 9.01 (s, 1 H) 9.11(s, 1 H)

Example 11.1(1H-BENZOIMIDAZOL-2-YL)-(3-{3-[4-(1-HYDROXY-ETHYL)-PHENYL]-PYRAZIN-2-YL}-AZETIDIN-1-YL)-METHANONE

1-(4-{3-[1-(1H-benzoimidazole-2-carbonyl)-azetidin-3-yl]-pyrazin-2-yl}-phenyl)-ethanone(100 mg, 0.25 mmol, Scheme 2, Example 2.21) was dissolved in 10 ml ofmethanol. This solution was cooled down to 0° C. using an ice bath andsodium tetraborohydride (19 mg, 0.50 mmol) was added by portions. Thereaction mixture was stirred for 4 h at ambient temperature, thensaturated aqueous solution of ammonium chloride (5 mL) was added. Themethanol was evaporated off under reduced pressure then the reactionmixture was taken up in ethyl acetate. The organic phase was separatedfrom the aqueous phase. This extraction was repeated one more time andthen the organic phases were combined and dried over magnesium sulphate,followed by concentrating under reduced pressure. The residue waspurified by column chromatography to give the title compound (75 mg,0.19 mmol, 75% yield).

The following Table 23A lists compounds of Examples 11.1 to 11.3, whichwere made analogous to Scheme 11 by using the appropriate materials andreaction conditions, which are listed in Table 23B. The NMR data of theExamples are listed in Table 23C.

TABLE 23A EXAMPLES 11.1 TO 11.3 ESI-MS IC₅₀ Ex. # Structure ChemicalName (M + 1) (uM) 11.1

(R & S)-(1H-Benzoimidazol-2- yl)-(3-{3-[4-(1-hydroxy-ethyl)-phenyl]-pyrazin-2-yl}-azetidin- 1-yl)-methanone 400 0.0288 11.2

(R & S)-(1H-Benzoimidazol-2- yl)-(3-{3-[3-(1-hydroxy-ethyl)-phenyl]-pyrazin-2-yl}-azetidin- 1-yl)-methanone 400 0.0778 11.3

(R & S)-(1H-Benzoimidazol-2- yl)-(3-{3-[4-(1-hydroxy-ethyl)-piperidin-1-yl]-pyrazin-2-yl}- azetidin-1-yl)-methanone 407 0.056

TABLE 23B STARTING MATERIALS AND REACTION CONDITION FOR PREPARATION OFEXAMPLES 11.1 TO 11.3. Unless otherwise stated, all starting materialsare commercially available from common vendors. Ex. # Starting Material1 Reaction Condition 11.1

NaBH₄, MeOH 0° C. 11.2

NaBH₄, MeOH 0° C. 11.3

NaBH₄, MeOH 0° C.

TABLE 23C 1H NMR δ (PPM) DATA FOR EXAMPLES 11.1 TO 11.3 Ex. # StructureNMR 11.1

(DMSO, 400 MHz): 8.65 (d, J = 2.4 Hz, 1H); 8.54 (d, J = 2.4 Hz, 1H);7.67-7.65 (m, 2 H); 7.56-7.54 (m, 2H); 7.49-7.47 (m, 2H); 7.37-7.34 (m,2H); 4.99-4.98 (m, 2H); 4.91-4.90 (m, 1H); 4.42-4.39 (m, 3H); 1.49 (d, J= 6.4 Hz, 3H). 11.2

(CDCl₃, 400 MHz): 8.44 (s, 2 H); 7.51 (brs, 2H); 7.36-7.35 (m, 3H);7.23-7.19 (m, 3H); 4.91-4.90 (m, 3H); 4.39-4.13 (m, 3H); 1.43 (d, J =6.0 Hz, 3H). 11.3

(CD₃OD, 400 MHz): 8.17 (d, J = 2.4 Hz, 1H); 8.11 (d, J = 2.4 Hz, 1H);7.67 (m, 2H), 7.26 (m, 2H); 5.18 (t, J = 7.6, 1H); 4.96(m, 1H); 4.62 (t,J = 8.0 Hz, 1H); 4.46-4.40 (m, 1H); 4.42-4.36 (m, 1H); 3.61-3.53 (m,1H); 3.45 (d, J = 8.4 Hz, 2H); 2.2.89-2.79 (m, 1H); 2.01-1.75 (m, 2H);1.61-1.42 (m, 2H) 1.38 (d, J = 6.4 Hz, 1H); 1.19(d, J = 6.4 Hz, 3H).

Example 12.11-(4-{3-[1-(1H-BENZOIMIDAZOLE-2-CARBONYL)-AZETIDIN-3-YL]-PYRAZIN-2-YL}-PIPERIDIN-1-YL)-ETHANONESTEP 1.4-{3-[1-(1H-BENZOIMIDAZOLE-2-CARBONYL)-AZETIDIN-3-YL]-PYRAZIN-2-YL}-3,6-DIHYDRO-2H-PYRIDINE-1-CARBOXYLICACID TERT-BUTYL ESTER

To a mixture of(1H-Benzoimidazol-2-yl)-[3-(3-chloro-pyrazin-2-yl)-azetidin-1-yl]-methanone(188 mg, 0.6 mmol) in 1,4-dioxane/water (5:1, 12 mL) was added4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3,6-dihydro-2H-pyridine-1-carboxylicacid tert-butyl ester (278 mg, 0.9 mmol), K₃PO₄ (254 mg, 1.2 mmol) andPd(dppf)Cl₂ (44 mg, 0.06 mmol). The mixture was refluxed overnight. Thereaction mixture was filtered and concentrated. The residue was purifiedby ISCO silica gel column (10% to 80% EtOAc in petroleum ether) to give4-{3-[1-(1H-benzoimidazole-2-carbonyl)-azetidin-3-yl]-pyrazin-2-yl}-3,6-dihydro-2H-pyridine-1-carboxylicacid tert-butyl ester (221 mg, 0.48 mmol, yield 80%). ESI-MS (M+1): 461calc. for C₂₅H₂₈N₆O₃ 460.

STEP 2.(1H-BENZOIMIDAZOL-2-YL)-{3-[3-(1,2,3,6-TETRAHYDRO-PYRIDIN-4-YL)-PYRAZIN-2-YL]-AZETIDIN-1-YL}-METHANONEHYDROCHLORIDE

To4-{3-[1-(1H-Benzoimidazole-2-carbonyl)-azetidin-3-yl]-pyrazin-2-yl}-3,6-dihydro-2H-pyridine-1-carboxylicacid tert-butyl ester (217 mg, 0.47 mmol) was added 4 M HCl in MeOH (100mL). The solution was stirred at RT for 2 h. The solvent was removedunder reduced pressure to give(1H-benzoimidazol-2-yl)-{3-[3-(1,2,3,6-tetrahydro-pyridin-4-yl)-pyrazin-2-yl]-azetidin-1-yl}-methanonehydrochloride (187 mg, 0.47 mmol, yield 100%). ESI-MS (M+1): 361 calc.for C₂₀H₂₀N₆O 360.

STEP 3.1-(4-{3-[1-(1H-BENZOIMIDAZOLE-2-CARBONYL)-AZETIDIN-3-YL]-PYRAZIN-2-YL}-3,6-DIHYDRO-2H-PYRIDIN-1-YL)-ETHANONE

To a solution of(1H-benzoimidazol-2-yl)-{3-[3-(1,2,3,6-tetrahydro-pyridin-4-yl)-pyrazin-2-yl]-azetidin-1-yl}-methanonehydrochloride (187 mg, 0.47 mmol) in dry CH₂Cl₂ (10 mL) was added Et₃N(1 mL). The reaction mixture was cooled to 0° C. with an ice bath, andacetyl chloride (39 mg, 0.50 mmol) was added dropwise. After 1 h, thereaction mixture was warmed to RT, and stirred overnight. Then thereaction mixture was washed with brine, dried over Na₂SO₄, filtered, andconcentrated under vacuum to give the crude product (170 mg, 0.42 mmol,90% yield). ESI-MS (M+1): 403 calc. for C₂₂H₂₂N₆O₂ 402.

STEP 4.1-(4-{3-[1-(1H-BENZOIMIDAZOLE-2-CARBONYL)-AZETIDIN-3-YL]-PYRAZIN-2-YL}-PIPERIDIN-1-YL)-ETHANONE

A mixture of1-(4-{3-[1-(1H-benzoimidazole-2-carbonyl)-azetidin-3-yl]-pyrazin-2-yl}-3,6-dihydro-2H-pyridin-1-yl)-ethanone(170 mg, 0.42 mmol) and wet Pd—C (50%, 50 mg) in MeOH (30 mL) wasstirred under H₂ (30 psi) at RT for 2 h then the reaction mixture wasfiltered through CELITE® and washed with MeOH. The filtrate wasconcentrated in vacuo and the residue was purified by ISCO silica gelcolumn (10% to 50% EtOAc in petroleum ether) to give1-(4-{3-[1-(1H-benzoimidazole-2-carbonyl)-azetidin-3-yl]-pyrazin-2-yl}-piperidin-1-yl)-ethanone(101 mg, 0.25 mmol, 60% yield).

¹H NMR (CDCl₃, 400 MHz): δ (ppm) 8.44 (dd, J=2.4, 4.0 Hz, 2H); 7.23-7.22(m, 2H); 7.39-7.37 (m, 2H); 5.36-5.34 (m, 1H); 5.08-5.05 (m, 1H);4.81-4.62 (m, 3H); 4.41-4.38 (m, 1H); 4.01 (d, J=13.2 Hz, 1H); 3.28-3.26(m, 1H); 3.06-3.01 (m, 1H); 2.79-2.77 (m, 1H); 2.20 (s, 3H); 2.04-2.01(m, 1H); 1.88-1.75 (m, 3H).

ESI-MS (M+1): 405. PDE10 IC₅₀ (uM): 0.427.

Examples 13.1 and 13.2

STEP 1.(1H-BENZOIMIDAZOL-2-YL)-{3-[3-(4-HYDROXY-PIPERIDIN-1-YL)-PYRAZIN-2-YL]-AZETIDIN-1-YL}-METHANONE

To a mixture of(1H-benzoimidazol-2-yl)-[3-(3-chloro-pyrazin-2-yl)-azetidin-1-yl]-methanone(0.170 g, 0.50 mmol) and piperidin-4-ol (0.101 g, 1.0 mmol) was addedtriethylamine (0.10 g, 1.0 mmol) and DMSO (4 mL). The solution washeated to 120° C. for 4 h. Then the mixture was diluted with water (10mL) and extracted with EtOAc (2×20 mL). The combined organic extractswere washed with water (10 mL) and brine (10 mL), dried over Na₂SO₄ andfiltered. The filtrate was evaporated in vacuo and the residue waspurified by flash column chromatography on silica gel (20% to 50% EtOAcin petroleum ether) to give(1H-benzoimidazol-2-yl)-{3-[3-(4-hydroxy-piperidin-1-yl)-pyrazin-2-yl]-azetidin-1-yl}-methanone(0.16 g, 0.42 mmol, 85% yield) as a white solid.

ESI-MS (M+1): 379 calc. for C₂₀H₂₂N₆O₂ 378.

STEP 2.1-{3-[1-(1H-BENZOIMIDAZOLE-2-CARBONYL)-AZETIDIN-3-YL]-PYRAZIN-2-YL}-PIPERIDIN-4-ONE

(1H-Benzoimidazol-2-yl)-{3-[3-(4-hydroxy-piperidin-1-yl)-pyrazin-2-yl]-azetidin-1-yl}-methanone(0.16 g, 0.42 mmol) was dissolved in anhydrous CH₂Cl₂ (20 mL), treatedwith Dess-Martin Periodinane (DMP) (195 mg, 0.46 mmol, 1.1 equiv) andstirred at RT until complete conversion controlled by TLC (Petroether:EtOAc=1:1). The organic layer was washed with an aqueous solutionof NaHCO₃/Na₂S₂O₃ (3×10 mL)), dried over Na₂SO₄, filtered andevaporated. The resulting residue was purified by flash chromatography(20% to 40% EtOAc in petroleum ether) to give1-{3-[1-(1H-benzoimidazole-2-carbonyl)-azetidin-3-yl]-pyrazin-2-yl}-piperidin-4-one(0.134 g, 0.36 mmol, 85% yield) as a white solid.

¹H NMR (CDCl₃, 400 MHz): δ (ppm) 8.24-8.14 (m, 2H); 7.71-7.68 (m, 2H);7.35-7.24 (m, 2H); 5.34-5.30 (m, 1H); 5.08-5.04 (m, 1H); 4.69-4.60 (m,2H); 4.39-4.31 (m, 1H); 3.55-3.44 (m, 4H); 2.67-2.57 (m, 4H).

ESI-MS (M+1): 377 calc. for C₂₀H₂₀N₆O₂ 376.

PDE10 IC₅₀ (uM): 0.0956.

STEP 3.(1H-BENZOIMIDAZOL-2-YL)-{3-[3-(4,4-DIFLUORO-PIPERIDIN-1-YL)-PYRAZIN-2-YL]-AZETIDIN-1-YL}-METHANONE

In a 50 mL flask,1-{3-[1-(1H-benzoimidazole-2-carbonyl)-azetidin-3-yl]-pyrazin-2-yl}-piperidin-4-one(0.134 g, 0.36 mmol) was dissolved in anhydrous CH₂Cl₂ (15 mL). Thesolution was cooled to −10° C. under nitrogen atmosphere and DAST (0.12g, 0.72 mmol) was added dropwise. The reaction mixture was allowed towarm to RT and stirred for 2 h. The mixture was poured into cold water(10 mL). The separated aqueous phase was extracted twice with CH₂Cl₂ (20mL), and the combined organic phases were dried over MgSO₄. Afterfiltration, the solvent was evaporated in vacuo, and the concentrate waspurified via flash chromatography on silica gel (20% to 45% EtOAc inpetroleum ether) to give(1H-benzoimidazol-2-yl)-{3-[3-(4,4-difluoro-piperidin-1-yl)-pyrazin-2-yl]-azetidin-1-yl}-methanone(0.114 g, 0.29 mmol, 80% yield) as a white solid.

¹H NMR (CDCl₃, 400 MHz): δ (ppm) 8.15 (d, J=1.6 Hz, 1H); 8.07 (d, J=2.4,1H); 7.64-7.62 (m, 2H); 7.29-7.26 (m, 2H); 5.26-5.22 (m, 1H); 5.00-4.96(m, 1H); 4.56-4.54 (m, 2H); 4.23-4.19 (m, 1H); 3.23-3.20 (m, 4H);2.12-2.04 (m, 4H).

ESI-MS (M+1): 399 calc. for C₂₀H₂₀F₂N₆O 398.

PDE10 IC₅₀ (uM): 0.0765.

Example 14.1(1H-BENZOIMIDAZOL-2-YL)-{3-[3-(4-HYDROXY-4-METHYL-PIPERIDIN-1-YL)-PYRAZIN-2-YL]-AZETIDIN-1-YL}-METHANONE

To a solution of1-{3-[1-(1H-benzoimidazole-2-carbonyl)-azetidin-3-yl]-pyrazin-2-yl}-piperidin-4-one(150 mg, 0.40 mol, SCHEME 13, Ex. 13.1) in 20 mL of THF was addedCH₃MgBr (0.60 mol, 3 M in ether) dropwise at 0° C. The mixture wasstirred for 1 h at RT and then quenched with saturated aqueous NH₄Cl.The resulting mixture was extracted with EtOAc (2×20 mL) and thecombined organic layers were dried over anhydrous Na₂SO₄, filtered andconcentrated to give crude product which was purified by prep.TLC(EtOAc:Petrol ether=1:1) to give(1H-benzoimidazol-2-yl)-{3-[3-(4-hydroxy-4-methyl-piperidin-1-yl)-pyrazin-2-yl]-azetidin-1-yl}-methanone(0.109 g, 0.28 mmol, 70% yield) as a white solid.

¹H NMR (CD₃OD, 400 MHz): δ (ppm) 8.12 (d, J=2.8 Hz, 1H); 8.05 (d, J=2.8Hz, 1H); 7.63-7.56 (m, 2H); 7.29-7.26 (m, 2H); 5.21-5.16 (m, 1H);4.57-4.54 (m, 2H); 3.28-3.20 (m, 2H); 3.11-3.08 (m, 2H); 1.81-1.70 (m,4H); 1.27 (s, 3H).

ESI-MS (M+1): 393. PDE10 IC₅₀ (uM): 0.131.

Example 15.1(1H-BENZOIMIDAZOL-2-YL)-[3-(5-PHENYL-PYRIMIDIN-4-YL)-AZETIDIN-1-YL]-METHANONESTEP 1. 3-(5-BROMO-2-CHLORO-PYRIMIDIN-4-YL)-AZETIDINE-1-CARBOXYLIC ACIDTERT-BUTYL ESTER

A 100 mL 3-neck round bottom flask fitted with a magnetic stirrer andflushed with nitrogen was charged with zinc dust (813 mg, preactivatedaccording to the above Preparation 1, 12.7 mmol) and DMA (10 mL,anhydrous). 1,2-dibromoethane (236 mg, 1.27 mmol) was added slowly,followed by TMSCl (137 mg, 1.27 mmol). The reaction was stirred for 15minutes at RT. A solution of N-Boc-3-iodoazetidine (2.7 g, 9.5 mmol) inDMA (10 mL, anhydrous) was added dropwise. The suspension was stirredfor 1 h at RT.

A 100 mL 3-neck round bottom flask fitted with a mechanical stirrer wascharged with 5-bromo-2,4-dichloro-pyrimidine (2 g, 4.42 mmol),Pd(dppf)Cl₂ (324 mg, 0.442 mmol), CuI (84 mg, 0.442 mmol), and DMA (20mL, anhydrous). The dark solution was degassed for 15 minutes. The clearzinc reagent solution above the residual solid zinc was transferred tothe above 100 mL flask by cannulation. The dark solution was degassedand heated to 80° C. for 16 h. The reaction was diluted with brine andextracted with EtOAc (3×100 mL). The combined organics were washed withwater (2×100 mL) and brine (100 mL), followed by drying over sodiumsulfate. The solution was concentrated and the residue was purified byflash column chromatography provides the title compound (0.7 g, 2.0mmol, yield: 46%). ESI-MS (M+1): 348 calc. for C₁₂H₁₅BrClN₃O₂ 347.

STEP 2. 4-AZETIDIN-3-YL-5-BROMO-2-CHLORO-PYRIMIDINE HYDROCHLORIDE

The mixture of3-(5-bromo-2-chloro-pyrimidin-4-yl)-azetidine-1-carboxylic acidtert-butyl ester (0.7 g, 2.0 mmol) in HCl/MeOH (10 mL) was stirred at RTfor 1 h. Then it was concentrated to give4-azetidin-3-yl-5-bromo-2-chloro-pyrimidine hydrochloride (0.57 g, 2.0mmol, yield 100%) which was used in the next step without furtherpurification. ESI-MS (M+1): 248 calc. for C₇H₇BrClN₃ 247.

STEP 3.(1H-BENZOIMIDAZOL-2-YL)-[3-(5-BROMO-2-CHLORO-PYRIMIDIN-4-YL)-AZETIDIN-1-YL]-METHANONE

To a solution of 4-azetidin-3-yl-5-bromo-2-chloro-pyrimidinehydrochloride (0.57 mg, 2.0 mmol) in DCM (20 mL) were added HATU (1.5 g,4.0 mmol), TEA (404 mg, 4 mmol) and 1H-benzoimidazole-2-carboxylic acid(398 mg, 2.4 mmol). The reaction mixture was stirred at RT for 12 h. TLCshowed that most of starting materials were consumed completely. Thenthe solution was washed with aqueous HCl (1 mol/L) (50 mL×3), saturatedaqueous NaHCO₃ (50 mL×3) and brine, dried over MgSO₄. The solution wasevaporated, the residue was purified by column chromatography to givethe product (206 mg, 0.53 mmol, yield: 27%). ESI-MS (M+1): 392 calc. forC₁₅H₁₁BrClN₅O 391

STEP 4.(1H-BENZOIMIDAZOL-2-YL)-[3-(2-CHLORO-5-PHENYL-PYRIMIDIN-4-YL)-AZETIDIN-1-YL]-METHANONE

A solution of(1H-benzoimidazol-2-yl)-[3-(5-bromo-2-chloro-pyrimidin-4-yl)-azetidin-1-yl]-methanone(206 mg, 0.53 mmol) in dioxane (15 mL) was treated with Na₂CO₃ (112 mg,1.1 mmol dissolved 1 mL of H₂O), followed by additional of phenylboronicacid (78 mg 0.64 mmol) and Pd(dppf)Cl₂ (37 mg, 0.05 mmol). The resultingmixture was heated at refluxing overnight under N₂ atmosphere. TLCshowed that most of the staring materials were consumed completely. Thesolution was filtered, and the filter was concentrated. And the residuewas purified by silica gel chromatography to give the product (102 mg,0.28 mmol, yield: 53%). ESI-MS (M+1): 362 calc. for C₂₁H₁₆ClN₅O 361.

STEP 5.(1H-BENZOIMIDAZOL-2-YL)-[3-(5-PHENYL-PYRIMIDIN-4-YL)-AZETIDIN-1-YL]-METHANONE

To a solution of(1H-Benzoimidazol-2-yl)-[3-(2-chloro-5-phenyl-pyrimidin-4-yl)-azetidin-1-yl]-methanone(102 mg, 0.28 mmol) in MeOH (10 mL) was added Pd/C (100 mg). Thereaction solution was stirred at RT overnight under H₂ atmosphere. Themixture was filtered and concentrated to give the product (51 mg, 0.16mmol, yield: 55%).

¹H NMR: (CDCl₃, 400 MHz): δ (ppm) 9.19 (s, 1H), 8.61 (s, 1H), 7.61-7.57(m, 2H), 7.49-7.41 (m, 5H), 7.31-7.18 (m, 2H), 5.07 (d, J=6.8 Hz, 2H),4.59-4.57 (m, 1H), 4.39-4.34 (m, 1H), 4.18-4.14 (m, 1H).

ESI-MS (M+1): 328.

PDE10 IC₅₀ (uM): 0.0291.

Example 16.12-(3-(3-(PROP-1-YN-1-YL)PYRAZIN-2-YL)AZETIDIN-1-YL)QUINOLINE

A mixture of 2-(3-(3-chloropyrazin-2-yl)azetidin-1-yl)quinoline (0.200g, 0.674 mmol), tributyl(prop-1-yn-1-yl)stannane (0.266 g, 0.809 mmol),and bis(tri-t-butylphosphine) palladium (o) (0.017 g, 0.034 mmol) inp-dioxane (4 mL) was heated at 100° C. in 16 h. The reaction mixture wascooled, concentrated, and purified by ISCO (0-60% EtOAc/Hexanes) to givethe title compound (128 mg, 68%).

¹H NMR (300 MHz, MeOH) 8.56 (1H, d, J=2.5 Hz), 8.44 (1H, d, J=2.5 Hz),8.04 (1H, d, J=9.1 Hz), 7.71 (2H, dd, J=7.8, 5.6 Hz), 7.58 (1H, td,J=7.7, 1.3 Hz), 7.27 (1H, t, J=7.5 Hz), 6.80 (1H, d, J=8.9 Hz),4.51-4.66 (5H, m), 2.21 (3H, s).

ESI-MS (M+1): 601. PDE10 IC₅₀ (μM): 0.077.

Example 17.1 2-[3-(3-M-TOLYL-PYRAZIN-2-YL)-AZETIDIN-1-YL]-QUINOLINE

To a solution of 2-azetidin-3-yl-3-m-tolyl-pyrazine hydrochloride (131mg, 0.05 mmol) and 2-chloro-quinoline (82 mg, 0.05 mmol) in DMF (10 mL)was added Cs₂CO₃ (325 mg, 1.0 mmol). The reaction mixture was stirred at100° C. overnight. The reaction mixture was diluted with water,extracted with EtOAc (30 mL×2). The combined organic extracts werewashed with water (30 mL) and brine (30 mL), dried over Na₂SO₄ andfiltered. The filtrate was evaporated in vacuo and the residue waspurified by flash column chromatography on silica gel (20% to 40% EtOAcin petroleum ether) to give2-[3-(3-m-tolyl-pyrazin-2-yl)-azetidin-1-yl]-quinoline (44 mg, 0.13mmol, 25%).

The following Table 24A lists compounds of Examples 17.1 to 17.6, whichwere made analogous to Scheme 17 by using the appropriate materials andreaction conditions, which are listed in Table 24B. The NMR data of theExamples are listed in Table 24C.

TABLE 24A EXAMPLES 17.1 TO 17.6 Ex. # Structure Chemical Name ESI-MS(M + 1) IC₅₀ (uM) 17.1

2-[3-(3-m-Tolyl- pyrazin-2-yl)-azetidin-1- yl]-quinoline 353 0.0017817.2

2-[3-(3-m-Tolyl- pyrazin-2-yl)-azetidin-1- yl]-quinazoline 354 0.01217.3

2-[3-(3-m-Tolyl- pyrazin-2-yl)-azetidin-1- yl]-quinoxaline 354 0.020917.4

2-[3-(3-m-Tolyl- pyrazin-2-yl)-azetidin-1- yl]-benzothiazole 359 0.031917.5

2-{3-[3-(3-Methoxy- phenyl)-pyrazin-2-yl]- azetidin-1-yl}-quinoline 3690.00299 17.6

2-{3-[3-(3-Methoxy- phenyl)-pyrazin-2-yl]- azetidin-1-yl}- quinazoline370 0.00929

TABLE 24B STARTING MATERIALS AND REACTION CONDITION FOR PREPARATION OFEXAMPLES 17.1 to 17.6. Ex. # Starting Material 1 Starting Material 2Reaction Condition 17.1

  31 PREPARATION 9

Cs₂CO₃, DMF, 100° C. 17.2 31 PREPARATION 9

Cs₂CO₃, DMF, 100° C. 17.3 31 PREPARATION 9

Cs₂CO₃, DMF, 100° C. 17.4 31 PREPARATION 9

ALDRICH Cs₂CO₃, DMF, 100° C. 17.5

  34 PREPARATION 10

Cs₂CO₃, DMF, 100° C. 17.6 34 PREPARATION 10

Cs₂CO₃, DMF, 100° C. Unless otherwise stated, all starting materials arecommercially available from common vendors.

TABLE 24C 1H NMR δ (PPM) DATA FOR EXAMPLES 17.1 TO 17.6 Ex. # StructureNMR 17.1

(CDCl₃, 400 MHz): 8.53-8.49 (m, 2H); 7.99 (d, J = 8.4 Hz, 1H); 7.92 (d,J = 8.4 Hz, 1H); 7.60 (t, J = 6.4 Hz, 2H); 7.33 (dd, J = 2.4, 7.6 Hz,2H); 7.24 (d, J = 7.6 Hz, 1H); 7.19 (s, 1H); 7.12 (d, J = 7.6 Hz, 1H);6.53 (d, J = 9.2 Hz, 1H); 4.89 (br s, 1H); 4.72-4.68 (m, 2H); 4.48-4.42(m, 2H); 2.37 (s, 3H) 17.2

CD₃OD, 400 MHz): 9.04 (s, 1H); 8.12 (d, J = 1.2 Hz, 1H); 8.49 (d, J =1.2 Hz, 1H); 7.71-7.67 (m, 2H); 7.54-7.52 (m, 1H); 7.41 (t, J = 7.6 Hz,1H); 7.33-7.26 (m, 2H); 7.285-7.23 (m, 2H); 4.38-4.36 (m, 5H); 2.43 (s,3H) 17.3

(CD₃OD, 400 MHz): 8.62 (d, J = 2.4 Hz, 1H); 8.52 (d, J = 2.4 Hz, 1H);8.17 (s, 1H), 7.79-7.76 (m, 1H); 7.61 (dd, J = 1.6, 8.8 Hz, 1H);7.57-7.52 (m, 1H); 7.43 (t, J = 7.6 Hz, 1H); 7.37-7.33 (m, 3H); 7.29 (d,J = 7.6 Hz, 1H); 4.44-4.39 (m, 5H); 2.45 (s, 3H). 17.4

(CD₃OD, 400 MHz): 8.63 (d, J = 1.2 Hz, 1H); 8.51 (d, J = 1.6 Hz, 1H);7.60 (d, J = 8.0 Hz, 1H); 7.44- 7.39 (m, 2H); 7.34-7.30 (m, 2H);7.27-7.22 (m, 2H); 7.06-7.02 (m, 1H); 4.44-4.40 (m, 1H); 4.35- 4.25 (m,4H); 2.43 (s, 3H). 17.5

(CD₃OD, 400 MHz): 8.54 (s, 1H); 8.50 (d, J = 0.8 Hz, 1H); 7.83 (d, J =8.8 Hz, 1H); 7.71 (d, J = 8.4 Hz, 1H); 7.57 (d, J = 8.0 Hz, 1H); 7.50(t, J = 7.2 Hz, 1H); 7.40 (t, J = 8.0 Hz, 1H); 7.18 (t, J = 7.2 Hz, 1H);7.05-7.00 (m, 3H); 6.60 (d, J = 8.8 Hz, 1H); 4.47-4.38 (m, 5H); 3.86 (s,3H). 17.6

(CDCl3, 400 MHz): 8.96 (s, 1H); 8.53 (d, J = 2.8 Hz, 1H); 8.46 (d, J =2.4 Hz, 1H); 7.62-7.55 (m, 3H); 7.38-7.33 (m, 1H) 7.16-7.13 (m, 1H);7.01- 6.95 (m, 3H); 4.51-4.41 (m, 4H); 4.35-4.29 (m, 1H); 3.80 (s, 3H).

Example 18.12-{3-[3-(3-METHOXY-PHENYL)-PYRIDIN-2-YL]-AZETIDIN-1-YL}-QUINOLINE

To a solution of 2-[3-(3-bromo-pyridin-2-yl)-azetidin-1-yl]-quinoline(339 mg, 1 mmol), 3-methoxy-phenylboronic acid (167.2 mg, 1.1 mmol),K₃PO₄ (414 mg, 2.0 mmol) in dioxane (20 mL) and water (2 mL) was addedPd(dppf)Cl₂ (36.6 mg, 0.05 mmol) then the reaction mixture was stirredat 90° C. under nitrogen atmosphere overnight. The reaction mixture wasfiltered through CELITE® and washed with EtOAc (50 mL). The filtrate wasconcentrated and the crude product was purified by ISCO silica gelcolumn (10% to 80% EtOAc in petroleum ether) to give2-{3-[3-(3-methoxy-phenyl)-pyridin-2-yl]-azetidin-1-yl}-quinoline (132mg, 0.36 mmol, yield 36%).

The following Table 25A lists compounds of Examples 18.1 to 18.2, whichwere made analogous to Scheme 18 by using the appropriate materials andreaction conditions, which are listed in Table 25B. The NMR data of theExamples are listed in Table 25C.

TABLE 25A EXAMPLES 18.1 TO 18.2 ESI- MS Ex. # Structure Chemical Name(M + 1) IC₅₀ (uM) 18.1

2-{3-[3-(3-Methoxy- phenyl)-pyridin-2-yl]- azetidin-1-yl}-quinoline 3680.00493 18.2

2-[3-(3-m-Tolyl-pyridin-2- yl)-azetidin-1-yl]-quinoline 352 0.00609

TABLE 25B STARTING MATERIALS AND REACTION CONDITION FOR PREPARATION OFEXAMPLES 18.1 TO 18.2. Ex. # Starting Material 1 Starting Material 2Reaction Condition 18.1

  PREPARATION 1

Pd(dppf)Cl₂, K₃PO₄, Dioxane/water 18.2

  PREPARATION 1

Pd(dppf)Cl₂, K₂PO₄, Dioxane/water Unless otherwise stated, all startingmaterials are commercially available from common vendors.

TABLE 25C 1H NMR δ (PPM) DATA FOR EXAMPLES 18.1 TO 18.2 Ex. # StructureNMR 18.1

(CDCl₃, 400 MHz): 8.79 (s, 1H); 8.03 (d, J = 9.2 Hz, 1H); 7.93 (d, J =8.0 Hz, 1H); 7.78 (d, J = 8.8 Hz, 1H); 7.66-7.62 (m, 2H); 7.59-7.56 (m,1H); 7.40-7.35 (m, 2H); 6.99-6.97 (m, 1H); 6.75 (t, J = 8.4 Hz, 2H);6.57 (d, J = 9.2 Hz, 1H); 4.75 (s, 3H); 4.54-4.52 (m, 2H); 3.79 (s, 3H).18.2

(CDCl₃, 400 MHz): 8.65 (s, 1H); 7.99 (d, J = 9.2 Hz, 1H); 7.88 (d, J =8.4 Hz, 1H); 7.67-7.59 (m, 3H); 7.35-7.30 (m, 3H); 7.22-7.19 (m, 1H);6.95 (d, J = 11.6 Hz, 2H); 6.54 (d, J = 5.2 Hz, 1H); 4.74 (s, 3H); 4.33(s, 2H); 2.37 (s, 3H).

Example 19.1 (R &S)-2-{3-[3-(3-METHYL-PYRROLIDIN-1-YL)-PYRIDIN-2-YL]-AZETIDIN-1-YL}-QUINOLINE

To a solution of 2-[3-(3-bromo-pyridin-2-yl)-azetidin-1-yl]-quinoline(339 mg, 1 mmol), 3-methyl-pyrrolidine (93.5 mg, 1.1 mmol), BINAP (31.1mg, 0.05 mmol), t-BuONa (196 mg, 2 mmol) in dioxane (25 mL) was addedPd₂(dba)₃ (45.75 mg, 0.05 mmol) then the reaction mixture was stirred at90° C. under nitrogen atmosphere overnight. The reaction mixture wasfiltered through CELITE® and washed with EtOAc (50 mL). The filtrate wasconcentrated and the crude product was purified by ISCO silica gelcolumn (10% to 80% EtOAc in petroleum ether) to give2-{3-[3-(3-methyl-pyrrolidin-1-yl)-pyridin-2-yl]-azetidin-1-yl}-quinoline(64 mg, 0.19 mmol, yield 19%).

The following Table 26A lists compounds of Examples 19.1 to 19.2, whichwere made analogous to Scheme 19 by using the appropriate materials andreaction conditions, which are listed in Table 26B. The NMR data of theExamples are listed in Table 26C.

TABLE 26A EXAMPLES 19.1 TO 19.2 ESI-MS Ex. # Structure Chemical Name(M + 1) IC₅₀ (uM) 19.1

(R & S)-2-{3-[3-(3-Methyl- pyrrolidin-1-yl)-pyridin-2-yl]-azetidin-1-yl}-quinoline 345 0.864  19.2

4-Methyl-2′-(1-quinolin-2-yl- azetidin-3-yl)-3,4,5,6- tetrahydro-2H-[1,3′]bipyridinyl 345 0.00522

TABLE 26B STARTING MATERIALS AND REACTION CONDITION FOR PREPARATION OFEXAMPLES 19.1 TO 19.2. Ex. # Starting Material 1 Starting Material 2Reaction Condition 19.1

  PREPARATION 1

Pd₂(dba)₃, BINAP, t- BuONa, dioxane 19.2

  PREPARATION 1

Pd₂(dba)₃, BINAP, t- BuONa, dioxane Unless otherwise stated, allstarting materials are commercially available from common vendors.

TABLE 26C 1H NMR δ (PPM) DATA FOR EXAMPLES 19.1 TO 19.2 Ex. # StructureNMR 19.1

(CDCl₃, 400 MHz): 8.22 (s, 1H); 8.02 (d, J = 9.2 Hz, 1H); 7.96 (d, J =8.4, 1H); 7.67-7.62 (m, 2H); 7.40-7.31 (m, 3H); 6.62 (d, J = 9.2 Hz,1H); 5.04-4.74 (m, 3H); 4.60-4.57 (m, 1H); 3.42 (s, 1H); 3.41-3.32 (m,1H); 3.27-3.18 (m, 1H); 2.91-2.86 (m, 1H); 2.39-2.33 (m, 1H); 2.14-2.09(m, 1H); 1.62-1.57 (m, 1H); 1.19 (s, 1H); 1.09 (d, J = 2.4 Hz, 3H). 19.2

(CDCl₃, 400 MHz): 8.32-8.31 (m, 1H); 7.85 (d, J = 8.8 Hz, 1H); 7.73 (d,J = 8.4 Hz, 1H), 7.60-7.58 (m, 1H); 7.53-7.51 (m, 1H); 7.34-7.32 (m,1H); 7.26-7.21 (m, 1H); 7.19-7.10 (m, 1H); 6.66 (d, J = 8.8 Hz, 1H);4.59- 4.52 (m, 3H); 4.51-4.47 (m, 2H); 2.81 (m, 4H); 1.79- 1.68 (m, 4H);1.62-1.56 (m, 2H).

Example 20.1{1-[3-(1-QUINOLIN-2-YL-PIPERIDIN-4-YL)-PYRAZIN-2-YL]-PIPERIDIN-4-YL}-METHANOL

To a solution of[1-(3-piperidin-4-yl-pyrazin-2-yl)-piperidin-4-yl]-methanolhydrochloride (156 mg, 0.5 mmol) and 2-chloro-quinoline (81.5 mg 0.5mmol) in DMF (5 mL) was added Cs₂CO₃ (325 mg, 1 mmol). The reactionmixture was stirred at 100° C. overnight. The reaction mixture wasdiluted with water, extracted with EtOAc (2×20 mL). The combined organicextracts were washed with water (15 mL) and brine (15 mL), dried overNa₂SO₄ and filtered. The filtrate was evaporated in vacuo and theresidue was purified by flash column chromatography on silica gel togive{1-[3-(1-quinolin-2-yl-piperidin-4-yl)-pyrazin-2-yl]-piperidin-4-yl}-methanol(142 mg, 0.35 mmol, yield 70.47%).

The following Table 27A lists compounds of Examples 20.1 to 20.10, whichwere made analogous to Scheme 20 by using the appropriate materials andreaction conditions, which are listed in Table 27B. The NMR data of theExamples are listed in Table 27C.

TABLE 27A EXAMPLES 20.1 TO 20.10 ESI-MS Ex. # Structure Chemical Name(M + 1) IC₅₀ (uM) 20.1 

{1-[3-(1-Quinolin-2-yl- piperidin-4-yl)-pyrazin- 2-yl]-piperidin-4-yl}-methanol 404 0.00172 20.2 

{1-[3-(1-Quinolin-2-yl- azetidin-3-yl)-pyrazin-2- yl]-piperidin-4-yl}-methanol 376 0.00114 20.3 

{1-[3-(1-Quinazolin-2- yl-azetidin-3-yl)- pyrazin-2-yl]-piperidin-4-yl}-methanol 377 0.00256 20.4 

4-[3-(1-Quinolin-2-yl- azetidin-3-yl)-pyrazin-2- yl]-phenylamine377 >10      20.5 

{1-[3-(1-Benzothiazol- 2-yl-azetidin-3-yl)- pyrazin-2-yl]-piperidin-4-yl}-meethanol 382 0.0323  20.6 

{1-[3-(1-Benzooxazol- 2-yl-azetidin-3-yl)- pyrazin-2-yl]-piperidin-4-yl}-methanol 366 2.170  20.7 

(1-{3-[1-(5-Methyl- pyridin-2-yl)-azetidin-3- yl]-pyrazin-2-yl}-piperidin-4-yl)-methanol 340 0.583  20.8 

2-(4-benzylpiperidin-1- yl)-3-(1-(quinolin-2- yl)azetidin-3-yl)quinoxaline 426 0.00243 20.9 

[5′-Fluoro-2′-(1- quinolin-2-yl-azetidin-3- yl)-3,4,5,6-tetrahydro-2H-[1,3′]bipyridinyl-4- yl]-methanol 393 0.181  20.10

{1-[3-(1-Quinolin-2-yl- azetidin-3-yl)-pyridazin- 4-yl]-piperidin-4-yl}-methanol 376 0.0322 

TABLE 27B STARTING MATERIALS AND REACTION CONDITION FOR PREPARATION OFEXAMPLES 20.1 TO 20.10. Ex. # Starting Material 1 Starting Material 2Reaction Condition 20.1 

  PREPARATION 12

Cs₂CO₃, DMF; 100° C. 20.2 

  PREPARATION 11

Cs₂CO₃, DMF; 100° C. 20.3 

  PREPARATION 11

Cs₂CO₃, DMF; 100° C. 20.4 

  PREPARATION 11

Cs₂CO₃, DMF; 100° C. 20.5 

  PREPARATION 11

  ALDRICH Cs₂CO₃, DMF; 100° C. 20.6 

  PREPARATION 11

Cs₂CO₃, DMF; 100° C. 20.7 

  PREPARATION 11

  ALDRICH Cs₂CO₃, DMF; 100° C. 20.8 

  PREPARATION 15

Cs₂CO₃, DMF; 100° C. 20.9 

  PREPARATION 23

Cs₂CO₃, DMF; 100° C. 20.10

  PREPARATION 18

Cs₂CO₃, DMF; 100° C. Unless otherwise stated, all starting materials arecommercially available from common vendors.

TABLE 27C 1H NMR δ (PPM) DATA FOR EXAMPLES 20.1 TO 20.10 Ex. # StructureName 20.1 

(CDCl₃, 400 MHz): 8.28-8.15 (m, 4H); 7.80-7.69 (m, 2H); 7.52-7.44 (m,1H); 7.14 (d, J = 8.0 Hz, 1H); 4.62 (s, 2H); 4.30 (d, J = 6.4 Hz, 1H);3.64 (d, J = 29.4 Hz, 3H); 3.44 (d, J = 7.6 Hz, 3H); 2.97-2.91 (m, 2H);2.10 (s, 4H); 1.90 (d, J = 6.4 Hz, 2H); 1.74 (s, 1H); 1.55 (d, J = 9.6Hz, 2H). 20.2 

(CDCl₃, 400 MHz): 8.15 (d, J = 2.4 Hz, 1H); 8.07 (d, J = 2.0 Hz, 1H);7.87 (d, J = 8.4 Hz, 1H); 7.74 (d, J = 8.4 Hz, 1H); 7.60 (d, J = 7.6 Hz,1H); 7.53 (t, J = 7.2 Hz, 1H); 7.23-7.19 (m, 1H); 6.65 (d, J = 8.8 Hz,1H); 4.55 (t, J = 8.0 Hz, 2H); 4.46 (t, J = 6.4 Hz, 2H); 4.34- 4.28 (m,1H); 3.58 (d, J = 6.0 Hz, 2H); 3.44 (d, J = 12.8 Hz, 2H); 2.89-2.92 (m,2H); 2.06 (s, 1H); 1.87 (d, J = 12.0 Hz, 1H); 1.74-1.68 (m, 1H);1.52-1.41 (m, 2H). 20.3 

(CD₃OD, 400 MHz): 9.01 (s, 1H); 8.06 (d, J = 2.8 Hz, 1H); 8.01 (d, J =2.4 Hz, 1H); 7.71 (dd, J = 2.4, 8.0 Hz, 1H); 7.67-7.63 (m, 1H); 7.49 (d,J = 8.4 Hz, 1H); 7.22-7.18 (m, 1H); 4.52 (t, J = 8.0 Hz, 2H); 4.36- 4.30(m, 2H); 4.28-4.26 (m, 1H); 3.40 (d, J = 6.4 Hz, 4H); 3.37 (s, 1H);2.81-2.74 (m, 2H); 1.81-1.78 (m, 2H); 1.61-1.54 (m, 1H); 1.43-1.39 (m,2H). 20.4 

(CD₃OD, 400 MHz): 8.91 (dd, J = 2.4, 7.2 Hz, 1H); 8.64 (dd, J = 0.8, 2.4Hz, 1H); 8.31 (s, 1H); 7.82 (d, J = 8.4 Hz, 1H); 7.67 (m, 1H); 7.66-7.59(m, 1H); 7.44- 7.40 (m, 1H); 4.73-4.72 (m, 1H); 4.31-4.25 (m, 4H);4.17-4.16 (m, 1H); 4.08-4.05 (m, 1H); 3.83-3.75 (m, 3H); 3.52 (d, J =6.4 Hz, 2H); 2.11-1.96 (m, 4H). 20.5 

(CD₃OD, 400 MHz): 8.22-8.20 (m, 1H); 8.17-8.15 (dd, J = 2.4, 8.4 Hz,1H); 7.87 (d, J = 8.0 Hz, 1H); 7.62-7.58 (m, 2H); 7.49-7.44 (m, 1H);4.62 (m, 1H); 4.54 (m, 1H); 4.32 (d, J = 6.8 Hz, 1H); 4.05-4.01 (m, 2H);3.94-3.89 (m, 1H); 3.54-3.51 (m, 1H); 3.47 (d, J = 10.4 Hz, 2H);3.02-2.90 (m, 2H); 1.93-1.86 (m, 2H); 1.58-1.45 (m, 3H). 20.6 

(CD₃OD, 400 MHz): 8.91 (d, J = 2.8 Hz, 1H); 8.66 (dd, J = 1.2, 2.8 Hz,1H); 7.33-7.30 (m, 2H); 7.20 (m, 1H); 7.10 (dd, J = 1.2, 4.0 Hz, 1H);4.25-4.10 (m, 5H); 3.96-3.91 (m, 1H); 3.83-3.74 (m, 3H); 3.65 (d, J =1.6 Hz, 2H); 2.14-1.89 (m, 5H). 20.7 

(CD₃OD, 400 MHz): 8.12 (d, J = 2.4 Hz, 1H); 8.07 (d, J = 2.4 Hz, 1H);7.83 (s, 1H); 7.43-7.40 (m, 1H); 6.42 (d, J = 8.8 Hz, 1H); 4.39-4.34 (m,3H); 4.18-4.15 (m, 2H); 3.48-3.43 (m, 4H); 2.87-2.80 (m, 2H); 2.18 (s,3H); 1.88-1.84 (m, 2H); 1.68-1.62 (m, 1H); 1.49-1.42 (m, 2H). 20.8 

(CD₃OD, 400 MHz): 8.34 (d, J = 8.0 Hz, 1H); 7.89 (s, 1H); 7.88 (t, J =1.2 Hz, 1H); 7.86 (t, J = 1.2 Hz, 1H); 7.81-7.78 (m, 2H); 7.70-7.66 (m,1H); 7.61-7.57 (m, 1H); 7.54-7.50 (m, 1H); 7.03 (d, J = 9.2 Hz, 1H);4.97-4.90 (m, 6H); 3.67 (d, J = 12.4 Hz, 2H); 3.54 (d, J = 6.0 Hz, 2H);3.05-2.99 (m, 2H); 1.98-1.94 (m, 2H); 1.76-1.73 (m, 2H). 20.9 

(CD₃OD, 400 MHz): 8.19-8.16 (m, 2H); 7.82 (d, J = 7.6 Hz, 1H); 7.77-7.71(m, 2H); 7.45 (t, J = 7.6 Hz, 1H); 7.37 (d, J = 10.4 Hz, 1H); 7.04 (d, J= 9.2 Hz, 1H); 6.04 (s, 1H); 5.74 (s, 1H); 4.72 (s, 2H); 3.47-3.43 (m,4H); 2.67 (t, J = 10.8 Hz, 2H); 1.83-1.80 (m, 2H); 1.60-1.57 (m, 1H);1.43-1.31 (m, 3H). 20.10

(CDCl₃, 400 MHz): 8.77 (s, 1H); 7.82 (d, J = 8.8 Hz, 1H); 7.66 (s, 1H);7.54 (d, J = 7.6 Hz, 1H); 7.46 (t, J = 7.6 Hz, 1H); 7.15 (t, J = 8.0 Hz,1H); 6.81 (t, J = 2.0 Hz, 1H); 6.61 (d, J = 8.8 Hz, 1H); 4.60-4.58 (m,4H); 4.41-4.16 (m, 1H); 3.55 (s, 2H); 3.23 (d, J = 12.4 Hz, 2H);2.70-2.68 (m, 2H); 1.86 (d, J = 12.0 Hz, 2H); 1.64 (s, 2H); 1.51-1.37(m, 1H)

Examples 21.2, 21.2 and 21.3 Racemic Mixture and Separated Enantiomers,wherein the Absolute Stereospecificity were not Determined

STEP 1. (R &S)-2-{3-[3-(3-METHYL-PYRROLIDIN-1-YL)-PYRAZIN-2-YL]-AZETIDIN-1-YL}-QUINOLINE

To a solution of 2-Azetidin-3-yl-3-(3-methyl-pyrrolidin-1-yl)-pyrazinehydrochloride (44) (127 mg, 0.5 mmol, PREPARATION 13) and2-chloro-quinoline (81.5 mg 0.5 mmol) in DMF (5 mL) was added Cs₂CO₃(325 mg, 1 mmol). The reaction mixture was stirred at 100° C. overnight.The reaction mixture was diluted with water, extracted with EtOAc (2×20mL). The combined organic extracts were washed with water (15 mL) andbrine (15 mL), dried over Na₂SO₄ and filtered. The filtrate wasevaporated in vacuo and the residue was purified by flash columnchromatography on silica gel to give(rac)-2-{3-[3-(3-methyl-pyrrolidin-1-yl)-pyrazin-2-yl]-azetidin-1-yl}-quinoline(127.65 mg, 0.37 mmol, yield 74%).

ESI-MS (M+1): 346. PDE10 IC₅₀ (uM): 0.00465.

(CDCl₃, 400 MHz): 8.05 (d, J=8.4 Hz, 1H); 8.00 (d, J=9.2 Hz, 1H); 7.93(d, J=2.4 Hz, 1H); 7.84 (d, J=2.4 Hz, 1H); 7.66-7.60 (m, 2H); 7.35 (t,J=7.6 Hz, 1H); 6.58 (d, J=9.6 Hz, 1H); 4.94-4.51 (m, 4H); 4.48-4.34 (m,1H); 3.45 (s, 3H); 3.08 (s, 1H); 2.31-2.25 (m, 1H); 2.09-2.02 (m, 1H);1.58-1.51 (m, 1H); 1.07 (d, J=6.8 Hz, 3H).

STEP 2. (R ORS)-2-{3-[3-(3-METHYL-PYRROLIDIN-1-YL)-PYRAZIN-2-YL]-AZETIDIN-1-YL}-QUINOLINE

The racemic2-{3-[3-(3-methyl-pyrrolidin-1-yl)-pyrazin-2-yl]-azetidin-1-yl}-quinolineobtained above (450 mg, 1.3 mmol) was separated by chiral prep. HPLC(Column: Chiralcel OD-H 250*30 mm, 5 u; Mobile phase: 85% hexane in EtOH(0.05% diethyl amine); Flow rate: 30 mL/minute) to give their separatedstereoisomers (187 mg, 0.54 mmol, 42% yield) and (175 mg, 0.50 mmol,38.5% yield). The absolute stereospecificity was not determined.Separated isomer Example 21.2: ESI-MS (M+1): 346. PDE10 IC₅₀ (uM):0.00367.

(CDCl₃, 400 MHz): 7.97-7.93 (m, 2H); 7.87 (d, J=8.8 Hz, 1H); 7.73 (d,J=8.4 Hz, 1H); 7.60 (d, J=8.0 Hz, 1H); 7.53 (t, J=8.4 Hz, 1H); 7.22 (t,J=7.6 Hz, 1H); 6.66 (d, J=9.2 Hz, 1H); 4.59-4.53 (m, 3H); 4.43 (t, J=8.0Hz, 1H); 4.33-4.26 (m, 1H); 3.66-3.48 (m, 3H); 3.18 (t, J=8.8 Hz, 1H);2.37-2.30 (m, 1H); 2.13-2.09 (m, 1H); 1.65-1.55 (m, 1H); 1.22 (d, J=6.8Hz, 3H).

Separated Isomer Example 21.3

ESI-MS (M+1): 346. PDE10 IC₅₀ (uM): 0.00367.

(CDCl₃, 400 MHz): 7.86-7.83 (m, 2H); 7.76 (d, J=8.8 Hz, 1H); 7.64 (d,J=8.4 Hz, 1H); 7.50 (d, J=7.6 Hz, 1H); 7.45-7.42 (m, 1H); 7.12 (t, J=8.4Hz, 1H); 6.55 (d, J=8.8 Hz, 1H); 4.48-4.43 (m, 3H); 4.18 (t, J=8.4 Hz,1H); 4.20-4.17 (m, 1H); 3.55-3.38 (m, 3H); 3.10-3.06 (m, 1H); 2.25-2.24(m, 1H); 2.03-1.99 (m, 1H); 1.52-1.47 (m, 1H); 1.05-1.04 (d, J=6.8 Hz,3H).

Example 22.1 2-(1-QUINOLIN-2-YL-AZETIDIN-3-YL)-3-M-TOLYL-QUINOXALINE

To a solution of 2-azetidin-3-yl-3-m-tolyl-quinoxaline hydrochloride(311 mg, 1 mmol) and 2-chloro-quinoline (163 mg, 1.0 mmol) in DMF (6 mL)was added Cs₂CO₃ (650 mg, 2 mmol). The reaction mixture was stirred at100° C. overnight. The reaction mixture was diluted with water,extracted with EtOAc (2×30 mL). The combined organic extracts werewashed with water (20 mL) and brine (20 mL), dried over Na₂SO₄ andfiltered. The filtrate was evaporated in vacuo and the residue waspurified by flash column chromatography on silica gel to give2-(1-quinolin-2-yl-azetidin-3-yl)-3-m-tolyl-quinoxaline (256 mg, 0.64mmol yield 63.7%).

The following Table 28A lists compounds of Examples 22.1 to 22.4, whichwere made analogous to Scheme 22 by using the appropriate materials andreaction conditions, which are listed in Table 28B. The NMR data of theExamples are listed in Table 28C.

TABLE 28A EXAMPLES 22.1 TO 22.4 ESI-MS Ex. # Structure Chemical Name(M + 1) IC₅₀ (uM) 22.1

2-(1-Quinolin-2-yl-azetidin- 3-yl)-3-m-tolyl-quinoxaline 403 0.0039922.2

4-[3-(1-Quinolin-2-yl- azetidin-3-yl)-quinoxalin-2- yl]-phenylamine 4040.00156 22.3

3-[3-(1-Quinolin-2-yl- azetidin-3-yl)-quinoxalin-2- yl]-phenol 4050.00099 22.4

2-(3-Methoxy-phenyl)-3-(1- quinolin-2-yl-azetidin-3-yl)- quinoxaline 4190.00222

TABLE 28B STARTING MATERIALS AND REACTION CONDITION FOR PREPARATION OFEXAMPLES 22.1 TO 22.4 Ex. # Starting Material 1 Starting Material 2Reaction Condition 22.1

  PREPARATION 20

Cs₂CO₃, DMF, 100° C. 22.2

  PREPARATION 20

Cs₂CO₃, DMF, 100° C. 22.3

  PREPARATION 20

Cs₂CO₃, DMF, 100° C. 22.4

  PREPARATION 20

Cs₂CO₃, DMF, 100° C. Unless otherwise stated, all starting materials arecommercially available from common vendors.

TABLE 28C 1H NMR δ (PPM) DATA FOR EXAMPLES 22.1 TO 22.4 Ex. # StructureNMR 22.1

(DMSO, 400 MHz): 8.15-8.08 (m, 2H); 8.01 (d, J = 8.0 Hz, 1H); 7.84-7.82(m, 2H); 7.68 (d, J = 7.6 Hz, 1H); 7.53-7.47 (m, 4H); 7.39- 7.31 (m,2H); 7.21-7.17 (m, 1H); 6.75 (d, J = 8.8 Hz, 1H); 4.58-4.54 (m, 1H);4.39 (t, J = 8.0 Hz, 2H); 4.26 (t, J = 8.4 Hz, 2H); 2.38 (s, 3H). 22.2

(CD₃OD, 400 MHz): 8.89 (d, J = 8.8 Hz, 1H); 8.11-8.08 (m, 2H); 7.86-7.82(m, 3H); 7.75- 7.72 (m, 4H); 7.49-7.42 (m, 3H); 6.92 (d, J = 9.2 Hz,1H); 4.85-4.68 (m, 5H). 22.3

(CD₃OD, 400 MHz): 8.29 (d, J = 9.2 Hz, 1H); 8.15-8.09 (m, 2H); 7.87-7.83(m, 3H); 7.78- 7.73 (m, 2H); 7.50-7.40 (m, 2H); 7.10-6.99 (m, 3H); 6.94(d, J = 9.2 Hz, 1H); 4.81-4.67 (m, 5H). 22.4

(CD₃OD, 400 MHz): 8.27 (d, J = 8.0 Hz, 1H); 8.25-8.28 (m, 2H); 7.86-7.82(m, 3H); 7.77- 7.71 (m, 2H); 7.53-7.46 (m, 2H); 7.21-7.13 (m, 3H); 6.93(d, J = 9.2 Hz, 1H); 4.81-4.66 (m, 5H); 3.88 (s, 3H).

Example 23.1 2-[3-(1-QUINOLIN-2-YL-AZETIDIN-3-YL)-PYRAZIN-2-YL]-PHENOL

To a solution of 2-(3-azetidin-3-yl-pyrazin-2-yl)-phenol hydrochloride(275 mg, 1 mmol) and 2-chloro-quinoline (163 mg, 1 mmol) in DMF (10 mL)was added Cs₂CO₃ (650 mg, 2 mmol). The reaction mixture was stirred at100° C. overnight. The reaction mixture was diluted with water,extracted with EtOAc (30 mL×2). The combined organic extracts werewashed with water (30 mL) and brine (30 mL), dried over Na₂SO₄ andfiltered. The filtrate was evaporated in vacuo and the residue waspurified by ISCO silica gel column (10% to 80% EtOAc in petroleum ether)to give 2-[3-(1-quinolin-2-yl-azetidin-3-yl)-pyrazin-2-yl]-phenol (56mg, 0.16 mmol, yield 16%).

The following Table 29A lists compounds of Examples 23.1 to 23.8, whichwere made analogous to Scheme 23 by using the appropriate materials andreaction conditions, which are listed in Table 29B. The NMR data of theExamples are listed in Table 29C.

TABLE 29A EXAMPLES 23.1 TO 23.8 ESI-MS IC₅₀ Ex. # Structure ChemicalName (M + 1) (uM) 23.1

2-[3-(1-Quinolin-2-yl- azetidin-3-yl)-pyrazin-2- yl]-phenol 355 0.0339 23.2

3-[3-(1-Quinolin-2-yl- azetidin-3-yl)-pyrazin-2- yl]-phenol 355 0.0046523.3

4-[3-(1-Quinolin-2-yl- azetidin-3-yl)-pyrazin-2- yl]-phenol 355 0.0044223.4

2-[3-(1-Quinolin-2-yl- azetidin-3-yl)-pyrazin-2- yl]-phenylamine 3540.133  23.5

3-[3-(1-Quinolin-2-yl- azetidin-3-yl)-pyrazin-2- yl]-phenylamine 3540.0111  23.6

4-[3-(1-Quinolin-2-yl- azetidin-3-yl)-pyrazin-2- yl]-phenylamine 3540.00522 23.7

2-{3-[3-(4-Fluoro-3- methoxy-phenyl)-pyrazin- 2-yl]-azetidin-1-yl}-quinoline 387 0.00298 23.8

2-Fluoro-4-[3-(1-quinolin- 2-yl-azetidin-3-yl)-pyrazin-2-yl]-phenylamine 372 0.00437

TABLE 29B STARTING MATERIALS AND REACTION CONDITION FOR PREPARATION OFEXAMPLES 23.1 TO 23.8. Unless otherwise stated, all starting materialsare commercially available from common vendors Reaction Ex. # StartingMaterial 1 Starting Material 2 Condition 23.1

Cs₂CO₃, DMF, 100° C. 23.2

Cs₂CO₃, DMF, 100° C. 23.3

Cs₂CO₃, DMF, 100° C. 23.4

Cs₂CO₃, DMF, 100° C. 23.5

Cs₂CO₃, DMF, 100° C. 23.6

Cs₂CO₃, DMF, 100° C. 23.7

Cs₂CO₃, DMF, 100° C. 23.8

Cs₂CO₃, DMF, 100° C.

TABLE 29C 1H NMR δ (PPM) DATA FOR EXAMPLES 23.1 TO 23.8 Ex. # StructureNMR 23.1

(CDCl₃, 400 MHz): 8.57 (s, 2H); 8.06 (d, J = 9.6 Hz, 1H); 7.94 (d, J =8.4 Hz, 1H); 7.73-7.68 (m, 2H); 7.45-7.41 (m, 1H); 7.35-7.31 (m, 1H);7.29-7.28 (m, 1H); 7.06 (d, J = 8.4 Hz, 1H); 7.02-6.98 (m, 1H); 6.62 (d,J = 9.6 Hz, 1H); 5.07 (s, 1H); 4.88-4.72 (m, 3H); 4.55 (s, 1H); 4.33 (s,1H) 23.2

(CD₃OD, 400 MHz): 8.68 (m, 1H); 8.52 (m, 1H); 8.49 (m, 1H); 8.28 (d, J =7.2 Hz, 1H); 7.79-7.71 (m, 2H); 7.51-7.47 (m, 1H); 7.39-7.35 (m, 1H);6.99-6.91 (m, 4H); 4.86-4.61 (m, 5H) 23.3

(CDCl₃, 400 MHz): 8.56-8.52 (m, 2H); 7.82 (d, J = 8.8 Hz, 1H); 7.95 (d,J = 8.4 Hz, 1H); 7.73- 7.67 (m, 2H); 7.42(t, J = 8.0 Hz, 1H); 7.19 (d, J= 8.0 Hz, 2H); 6.88 (d, J = 8.8 Hz, 2H); 6.62 (d, J = 9.2 Hz, 1H); 4.73(m, 2H); 4.36 (m, 1H); 4.19 (s, 2H). 23.4

(CDCl₃, 400 MHz): 8.49 (s, 1H); 8.41 (s, 1H); 7.65 (d, J = 8.8 Hz, 1H);7.51 (d, J = 8.0 Hz, 1H); 7.46 (d, J = 1.2 Hz, 1H); 7.45-7.42 (m, 1H);7.12-7.10 (m, 2H); 6.94 (dd, J = 7.6 Hz, 1H); 6.81-6.75 (m, 2H); 6.52(d, J = 8.8 Hz, 1H); 4.37-4.21 (m, 5H); 4.13 (s, 2H) 23.5

(CDCl₃, 400 MHz): 8.61-8.52 (m, 2H); 8.05 (d, J = 9.6 Hz, 1H); 8.00 (d,J = 8.4 Hz, 1H); 7.69- 7.69 (m, 2H); 7.41-7.26 (m, 2H); 7.02-6.98 (m,2H); 6.91-6.90 (m, 1H); 6.62 (d, J = 9.2 Hz, 1H); 4.85-4.31 (m, 5H).23.6

(CD₃OD, 400 MHz): 8.63 (d, J = 2.4 Hz, 1H); 8.56 (d, J = 2.4 Hz, 1H);8.31 (d, J = 9.2 Hz, 1H); 7.89 (d, J = 8.4 Hz, 1H); 7.78-7.75(m, 2H);7.50 (m, 1H); 7.45 (d, J = 8.4 Hz, 2H); 7.06 (d, J = 8.4 Hz, 2H); 6.94(d, J = 9.6 Hz, 1H); 4.70 (s, 5H). 23.7

(CDCl3, 400 MHz): 8.63 (d, J = 2.4 Hz, 1H); 8.57 (d, J = 2.0 Hz, 1H);7.90 (d, J = 8.0 Hz, 1H); 7.76 (d, J = 9.2 Hz, 1H); 7.64 (dd, J = 1.2,8.0 Hz, 1H); 7.59-7.55 (m, 1H); 7.28-7.20 (m, 3H); 7.06-7.03 (m, 1H);6.67 (d, J = 8.8 Hz, 1H); 4.49-4.45 (m, 5H); 4.01 (s, 3H) 23.8

(CDCl3, 400 MHz): 8.43 (d, J = 2.0 Hz, 1H); 8.41 (d, J = 2.0 Hz, 1H);7.80 (d, J = 8.8 Hz, 1H); 7.66 (d, J = 8.4 Hz, 1H); 7.53 (dd, J = 1.2,8.0 Hz, 1H); 7.48-7.44 (m, 1H); 7.17-7.13 (m, 2H); 7.06-7.03 (m, 1H);6.81 (t, J = 8.8 Hz, 1H); 6.55 (d, J = 8.8 Hz, 1H); 4.38-4.35 (m, 5H);4.01 (s, 2H)

Example 24.12-[3-(3-PIPERIDIN-1-YL-PYRAZIN-2-YL)-AZETIDIN-1-YL]-QUINOLINE

To a solution of 2-azetidin-3-yl-3-piperidin-1-yl-pyrazine hydrochloride(127 mg, 0.5 mmol) and 2-chloro-quinoline (81.5 mg 0.5 mmol) in DMF (5mL) was added Cs₂CO₃ (325 mg, 1 mmol). The reaction mixture was stirredat 100° C. overnight. The reaction mixture was diluted with water,extracted with EtOAc (2×20 mL). The combined organic extracts werewashed with water (15 mL) and brine (15 mL), dried over Na₂SO₄ andfiltered. The filtrate was evaporated in vacuo and the residue waspurified by ISCO silica gel column (10% to 80% EtOAc in petroleum ether)to give 2-[3-(3-piperidin-1-yl-pyrazin-2-yl)-azetidin-1-yl]-quinoline(58 mg, 0.17 mmol yield 17%).

The following Table 30A lists compounds of Examples 24.1 to 24.7, whichwere made analogous to Scheme 24 by using the appropriate materials andreaction conditions, which are listed in Table 30B. The NMR data of theExamples are listed in Table 30C.

TABLE 30A EXAMPLES 24.1 TO 24.7 ESI-MS Ex. # Structure Chemical Name(M + 1) IC₅₀ (uM) 24.1

2-[3-(3-Piperidin-1-yl- pyrazin-2-yl)-azetidin-1- yl]-quinoline 3460.00393 24.2

2-{3-[3-(4-Methyl- piperidin-1-yl)-pyrazin-2-yl]-azetidin-1-yl}-quinoline 368 0.000803 24.3

1-[3-(1-Quinolin-2-yl- azetidin-3-yl)-pyrazin-2-yl]-piperidine-4-carboxylic acid amide 389 0.00048 24.4

1-[3-(1-Quinolin-2-yl- azetidin-3-yl)-pyrazin-2-yl]-piperidine-4-carboxylic acid dimethylamide 417 0.00355 24.5

1-[3-(1-Quinolin-2-yl- azetidin-3-yl)-pyrazin-2yl]-piperidine-4-carboxylic acid methylamide 403 0.00251 24.6

1-[3′-(1-Quinolin-2-yl- azetidin-3-yl)-2,3,5,6- tetrahydro-[1,2′]bipyrazinyl-4-yl]- ethanone 389 0.029 24.7

1-[3-(1-Quinolin-2-yl- azetidin-3-yl)-pyrazin-2- yl]-piperidin-4-ol 3620.00497

TABLE 30B STARTING MATERIALS AND REACTION CONDITION FOR PREPARATION OFEXAMPLES 24.1 TO 24.7. Unless otherwise stated, all starting materialsare commercially available from common vendors. Reaction Ex. # StartingMaterial 1 Starting Material 2 Condition 24.1

Cs₂CO₃, DMF, 100° C. 24.2

Cs₂CO₃, DMF, 100° C. 24.3

Cs₂CO₃, DMF, 100° C. 24.4

Cs₂CO₃, DMF, 100° C. 24.5

Cs₂CO₃, DMF, 100° C. 24.6

Cs₂CO₃, DMF, 100° C. 24.7

Cs₂CO₃, DMF, 100° C.

TABLE 30C 1H NMR δ (PPM) DATA FOR EXAMPLES 24.1 TO 24.7 Ex. # StructureNMR 24.1

(CDCl₃, 400 MHz): 8.12 (s, 2H); 8.05 (d, J = 20.8 Hz, 1H); 7.96 (d, J =8.4 Hz, 1H); 7.67-7.63 (m, 2H); 7.40- 7.36 (m, 1H); 6.62 (d, J = 9.2 Hz,1H); 5.07 (s, 1H); 4.75-4.71 (m, 3H); 4.39-4.36 (m, 1H); 3.06-3.04 (m.4H); 1.75-1.69 (m, 4H); 1.64-1.62 (m, 2H). 24.2

(CDCl₃, 400 MHz): 8.12 (d, J = 2.4 Hz, 1H); 8.06 (d, J = 2.4 Hz, 1H);7.85 (d, J = 8.8 Hz, 1H); 7.74 (d, J = 8.4 Hz, 1H); 7.58 (d, J = 8.0 Hz,1H); 7.50 (d, J = 2.8 Hz, 2H); 7.20-7.18 (m, 1H); 6.64 (d, J = 8.8 Hz,1H); 4.56- 4.52 (m, 2H); 4.47-4.43 (m, 2H); 4.33-4.26 (m, 1H); 3.38 (d,J = 12.8 Hz, 2H); 2.83 (t, J = 12.0 Hz, 2H); 1.77 (d, J = 12.4 Hz, 2H);1.57 (s, 1H); 1.44-1.35 (m, 2H); 1.01 (d, J = 6.4 Hz, 3H). 24.3

(CDCl3, 400 MHz): 8.21 (m, 2H); 8.19 (dd, J = 2.4, 7.2 Hz, 2H); 8.09 (d,J = 9.2 Hz, 1H); 8.06 (d, J = 8.4 Hz, 1H); 7.75-7.69 (s, 1H); 6.68-6.66(d, J = 9.2 Hz, 1H); 5.84 (s, 1H); 4.98 (s, 1H); 4.69 (m, 2H); 4.47-4.43(m, 1H); 3.45 (d, J = 12.4 Hz, 2H); 2.89 (m, 2H); 2.42-2.41 (m, 1H);2.06-2.04 (m, 4H) 24.4

(CD₃OD, 400 MHz): 8.31 (d, J = 9.6 Hz, 1H); 8.20 (dd, J = 2.4, 15.6 Hz,2H); 7.87 (d, J = 8.0 Hz, 1H); 7.80-7.74 (m, 2H); 7.51-7.47 (m, 1H);6.98 (d, J = 9.6 Hz. 1H); 4.90 (t, J = 9.2 Hz, 2H); 4.73 (t, J = 7.8 Hz,2H); 4.60- 4.57 (m, 1H); 3.49 (d, J = 12.8 Hz, 2H); 3.14 (s, 3H);3.01-2.91 (m, 5H); 2.43-2.38 (m, 1H); 1.94-1.85 (m, 4H). 24.5

(CD₃OD, 400 MHz): 8.33 (d, J = 9.6 Hz, 1H); 8.23 (d, J = 2.4 Hz, 1H);8.19 (d, J = 2.4 Hz, 1H); 7.89 (d, J = 7.6 Hz, 1H); 7.79-7.76 (m, 2H);7.53-7.49 (m, 1H); 7.00 (d, J = 9.6 Hz, 1H); 4.93-4.89 (m, 2H); 4.74 (t,J = 6.4 Hz, 2H); 4.60-4.56 (m, 1H); 3.50-3.47 (d, J = 12.8 Hz, 2H);2.93-2.91 (m, 2H); 2.75 (s, 3H); 2.43-2.38 (m, 1H); 1.93- 1.98 (m, 4H).24.6

(MeOD, 400 MHz): 8.32 (d, J = 9.6 Hz, 1H); 8.28 (d, J = 2.4 Hz, 1H);8.22 (d, J = 2.4 Hz, 1H); 7.88 (d, J = 8.0 Hz, 1H); 7.80-7.74 (m, 2H);7.52-7.48 (m, 1H); 6.99 (d, J = 9.6 Hz. 1H); 4.91 (d, J = 9.2 Hz, 2H);4.75 (s, 2H); 4.63-4.59 (m, 1H); 3.79-3.73 (m, 4H); 3.23 (t, J = 5.2 Hz,2H); 3.14 (t, J = 5.2 Hz, 2H); 2.15 (s, 3H). 24.7

(MeOD, 400 MHz): 8.07-8.02 (m, 2H); 7.94 (d, J = 9.2 Hz, 1H); 7.59 (d, J= 8.8 Hz, 2H); 7.47 (t, J = 6.4 Hz, 1H); 7.16 (t, J = 6.0 Hz, 1H); 6.69(d, J = 9.2 Hz, 1H); 4.52 (s, 2H); 4.35-3.34 (m, 3H); 3.75-3.68 (m, 1H);3.37- 3.29 (m, 2H); 2.89 (m, 2H); 1.95-1.89 (m, 2H); 1.69- 1.65 (m, 2H).

Example 25.12-METHOXY-1-{4-[3-(1-QUINOLIN-2-YL-AZETIDIN-3-YL)-PYRAZIN-2-YL]-PIPERIDIN-1-YL}-ETHANONE

A solution of 2-azetidin-3-yl-3-chloro-pyrazine hydrochloride (190 mg,0.5 mmol) and Et₃N (101 mg, 1 mL,) in DCM (15 mL) was addedmethoxy-acetyl chloride (purchased from ALDRICH) (81 mg, 0.75 mmol). Thereaction was stirred at RT for 2 h. The reaction mixture wasconcentrated and purified by ISCO silica gel column (10% to 80% EtOAc inpetroleum ether) give the product2-methoxy-1-{4-[3-(1-quinolin-2-yl-azetidin-3-yl)-pyrazin-2-yl]-piperidin-1-yl}-ethanone(82 mg, 0.20 mmol, 39% yield).

The following Table 31A lists compounds of Examples 25.1 to 25.4, whichwere made analogous to Scheme 25 by using the appropriate materials andreaction conditions, which are listed in Table 31B. The NMR data of theExamples are listed in Table 31C.

TABLE 31A EXAMPLES 25.1 TO 25.4 ESI-MS Ex. # Structure Chemical Name(M + 1) IC₅₀ (uM) 25.1

2-Methoxy-1-{4-[3-(1- quinolin-2-yl-azetidin-3- yl)-pyrazin-2-yl]-piperidin-1-yl}-ethanone 418 0.0636 25.2

1-{4-[3-(1-Quinolin-2-yl- azetidin-3-yl)-pyrazin-2- yl]-piperidin-1-yl}-ethanone 388 0.0342 25.3

N-{4-[3-(1-Quinolin-2-yl- azetidin-3-yl)-pyrazin-2-yl]-phenyl}-acetamide 396 0.00236 25.4

1-(4-(3-(1-(quinolin-2- yl)azetidin-3-yl)pyrazin-2-yl)-5,6-dihydropyridin- 1(2H)-yl)ethanone 386 0.0006

TABLE 31B STARTING MATERIALS AND REACTION CONDITION FOR PREPARATION OFEXAMPLES 25.1 TO 25.4. Unless otherwise stated, all starting materialsare commercially available from common vendors. Ex. # Starting Material1 Starting Material 2 Reaction Condition 25.1

Et₃N, DCM 25.2 54 PREPARATION 16

Et₃N, DCM 25.3

Et₃N, DCM 25.4

Et₃N, DCM

TABLE 31C 1H NMR δ (PPM) DATA FOR EXAMPLES 25.1 TO 25.4 Ex. # StructureNMR 25.1

(CD₃OD, 400 MHz): 8.41-8.38 (m, 2H); 7.97 (t, J = 7.6 Hz, 1H); 7.64 (t,J = 8.8 Hz, 2H); 7.54-7.50 (m, 1H); 7.24-7.19 (m, 1H); 6.72 (t, J = 8.8Hz, 1H); 4.64-4.44 (m, 6H); 4.22-4.11 (m, 2H); 3.97 (d, J = 13.2 Hz,1H); 3.42 (s, 3H); 3.30-3.15 (m, 2H); 2.84-2.82 (m, 1H); 1.82- 1.78 (m,4H) 25.2

(CDCl₃, 400 MHz): 8.35-8.33 (m, 2H); 7.85 (d, J = 8.8 Hz, 1H); 7.72 (d,J = 8.4 Hz, 1H); 7.55 (dd, J = 1.2, 8.0 Hz, 1H); 7.51-7.47 (m, 1H);7.21-7.17 (m, 1H); 6.61 (d, J = 8.8 Hz, 1H); 4.73 (d, J = 12.4 Hz, 1H);4.60-4.47 (m, 4H); 4.36-4.32 (m, 1H); 3.94-3.91 (m, 1H), 3.19-3.13 (m,1H); 2.95-2.88 (m, 1H); 2.64-3.63 (m, 1H); 2.07 (s, 3H); 2.03-2.00 (m,1H); 1.77-1.71 (m, 3H). 25.3

(CD₃OD, 400 MHz): 8.53-8.44 (m, 2H); 7.94 (d, J = 9.2 Hz, 1H); 7.69 (d,J = 8.4 Hz, 2H); 7.60-7.56 (m, 2H); 7.47-7.42 (m, 3H); 7.18 (t, J = 7.6Hz, 1H); 6.64 (d, J = 9.2 Hz, 1H); 4.39- 4.33 (m, 5H); 2.08 (s, 3H).25.4

(400 MHz, chloroform-d) 2.19 (d, J = 5.87 Hz, 3 H) 2.69 (br. S., 2H)3.72 (t, J = 5.58 Hz, 1 H) 3.89 (t, J = 5.58 Hz, 1 H) 4.19 (d, J = 2.54Hz, 1 H) 4.31 (d, J = 2.54 Hz, 1 H) 4.36-4.56 (m, 5 H) 5.77-5.88 (m, 1H) 6.65 (dd, J = 8.90, 2.25 Hz, 1 H) 7.22 (t, J = 7.43 Hz, 1 H) 7.53 (t,J = 7.63 Hz, 1 H) 7.61 (d, J = 8.02 Hz, 1 H) 7.74 (d, J = 8.41 Hz, 1 H)7.89 (dd, J = 8.90, 3.03 Hz, 1 H) 8.42 (t, J = 2.93 Hz, 1 H) 8.49 (d, J= 2.54 Hz, 1H).

Examples 26.1, 26.2, and 26.3 Racemic Mixtures and SeparatedEnantiomers, Absolute Stereochemistry not Further Determined STEP 1.1-{1-[3-(1-QUINOLIN-2-YL-AZETIDIN-3-YL)-PYRAZIN-2-YL]-PIPERIDIN-4-YL}-ETHANONE

To a solution of 2-[3-(3-chloro-pyrazin-2-yl)-azetidin-1-yl]-quinoline(80 mg, 0.27 mmol) and 1-piperidin-4-yl-ethanone (WUXI APPTEC) (34.3 mg,0.27 mmol) in DMSO (5 mL) was added Et₃N (54.5 mg, 0.54 mmol). Thereaction mixture was stirred at 100° C. overnight. The reaction mixturewas diluted with water, extracted with EtOAc (20 mL×3). The combinedorganic extracts were washed with water (30 mL) and brine (30 mL), driedover Na₂SO₄ and filtered. The filtrate was evaporated in vacuo and theresidue was purified by flash column chromatography on silica gel togive1-{1-[3-(1-quinolin-2-yl-azetidin-3-yl)-pyrazin-2-yl]-piperidin-4-yl}-ethanone(65.8 mg, 0.17 mmol, yield 62.9%).

ESI-MS (M+1): 388 calc. for C₂₃H₂₅N₅O 387.

STEP 2. (S &R)-1-{1-[3-(1-QUINOLIN-2-YL-AZETIDIN-3-YL)-PYRAZIN-2-YL]-PIPERIDIN-4-YL}-ETHANOL

A solution of1-{1-[3-(1-quinolin-2-yl-azetidin-3-yl)-pyrazin-2-yl]-piperidin-4-yl}-ethanone(96.75 mg, 0.25 mmol) in MeOH (10 mL) was added NaBH₄ (37 mg, 1 mmol).The mixture was stirred at RT for 2 h. The reaction mixture wasconcentrated to give the product(racemic)-1-{1-[3-(1-quinolin-2-yl-azetidin-3-yl)-pyrazin-2-yl]-piperidin-4-yl}-ethanol(76 mg, 0.20 mmol, yield 78%).

ESI-MS (M+1): 390. PDE10 IC₅₀ (uM): 0.00805.

(CD₃OD, 400 MHz): 8.31 (d, J=9.2 Hz, 1H); 8.22-8.16 (m, 2H); 7.88 (d,J=7.6 Hz, 1H); 7.78-7.75 (m, 2H); 7.52-7.48 (m, 1H); 6.98 (d, J=9.6 Hz,1H); 4.89 (d, J=7.2 Hz, 1H); 4.72 (t, J=7.2 Hz, 2H); 4.56-4.55 (m, 1H);3.60-3.57 (m, 1H); 3.47 (d, J=12.8 Hz, 2H); 2.87-2.84 (m, 2H); 1.98-1.97(m, 1H); 1.77-1.76 (m, 1H); 1.56-1.48 (m, 3H); 1.47 (d, J=3.2 Hz, 1H);1.20 (d, J=6.4 Hz, 3H).

Examples 26.2 and 26.3 STEP 3. SEPARATED R ANDS-1-{1-[3-(1-QUINOLIN-2-YL-AZETIDIN-3-YL)-PYRAZIN-2-YL]-PIPERIDIN-4-YL}-ETHANOL

The racemic mixture of1-{1-[3-(1-quinolin-2-yl-azetidin-3-yl)-pyrazin-2-yl]-piperidin-4-yl}-ethanol(450 mg, 1.16 mmol) was separated by chiral prep. HPLC (Column:Chiralpak AD-H 250*30 mm, 5 u; Mobile phase: 70% hexane in EtOH (0.05%diethyl amine); Flow rate: 20 mL/minute) to give their separatedenantiomers (152 mg, 0.41 mmol, 34% yield) and 182 mg, 0.47 mmol, 41%yield).

Separated Isomer Example 26.2

ESI-MS (M+1): 390. PDE10 IC₅₀ (uM): 0.00237.

¹H NMR δ (ppm) (CDCl₃, 400 MHz): 8.16-8.08 (m, 2H); 7.88 (d, J=8.8 Hz,1H); 7.73 (d, J=8.4 Hz, 1H); 7.62-7.59 (m, 1H); 7.55-7.51 (m, 1H);7.24-7.20 (m, 1H); 6.66 (d, J=8.8 Hz, 1H); 4.57-4.53 (m, 2H); 4.48-4.45(m, 2H); 4.34-4.32 (m, 1H); 3.70-3.68 (m, 1H); 3.50-3.46 (m, 2H);2.88-2.81 (m, 2H); 2.02-1.99 (m, 1H); 1.79-1.76 (m, 1H); 1.58-1.49 (m,3H); 1.25 (d, J=6.4 Hz, 3H).

Separated Isomer Example 26.3

ESI-MS (M+1): 390. PDE10 IC₅₀ (uM): 0.00262.

¹H NMR δ (ppm) (CDCl₃, 400 MHz): 8.15-8.08 (m, 2H); 7.88 (d, J=8.8 Hz,1H); 7.73 (d, J=8.4 Hz, 1H); 7.61-7.55 (m, 1H); 7.53-7.51 (m, 1H);7.23-7.19 (m, 1H); 6.66 (d, J=9.2 Hz, 1H); 4.57-4.53 (m, 2H); 4.48-4.44(m, 2H); 4.35-4.29 (m, 1H); 3.69-3.67 (m, 1H); 3.49-3.46 (m, 2H);2.87-2.81 (m, 2H); 2.02-1.99 (m, 1H); 1.79-1.76 (m, 1H); 1.57-1.51 (m,3H); 1.25 (d, J=6.4 Hz, 3H).

Example 27.12-FLUORO-5-[3-(1-QUINOLIN-2-YL-AZETIDIN-3-YL)-PYRAZIN-2-YL]-PHENOL

To a solution of2-{3-[3-(4-fluoro-3-methoxy-phenyl)-pyrazin-2-yl]-azetidin-1-yl}-quinoline(193 mg, 0.5 mmol) in 1,2-dichloro-ethane (5 mL) was added BBr₃ (250 mg,1.0 mmol). The reaction mixture was stirred at RT for 2 h. The reactionmixture was diluted with water, extracted with DCM (2×30 mL). Thecombined organic extracts were washed with water (20 mL) and brine (20mL), dried over Na₂SO₄ and filtered. The filtrate was evaporated invacuo and the residue was purified by flash column chromatography onsilica gel to give2-fluoro-5-[3-(1-quinolin-2-yl-azetidin-3-yl)-pyrazin-2-yl]-phenol (111mg, 0.31 mmol yield 62%).

ESI-MS (M+1): 373. PDE10 IC₅₀ (uM): 0.00284.

¹H NMR δ (ppm) (CD₃OD, 400 MHz): 8.63-8.57 (m, 2H); 8.29 (d, J=8.0 Hz,1H); 7.87 (d, J=8.0 Hz, 1H); 7.79-7.72 (m, 2H); 7.52-7.48 (m, 1H);7.26-7.21 (m, 1H); 7.15-7.13 (m, 1H); 7.00-6.96 (m, 1H); 6.93 (d, J=9.2Hz, 1H); 4.68-4.64 (m, 5H).

Example 28.1(1-{3-[1-(6-METHYL-QUINOLIN-2-YL)-AZETIDIN-3-YL]-PYRAZIN-2-YL}-PIPERIDIN-4-YL)-METHANOL

To a solution of[1-(3-azetidin-3-yl-pyrazin-2-yl)-piperidin-4-yl]-methanol hydrochloride(284 mg, 1.0 mmol) and 2-chloro-6-methyl-quinoline (purchased fromALDRICH) (177 mg, 1.0 mmol) in DMF (15 mL) was added Cs₂CO₃ (650 mg, 2.0mmol). The reaction mixture was stirred at 100° C. overnight. Thereaction mixture was diluted with water, extracted with EtOAc (2×30 mL).The combined organic extracts were washed with water (20 mL) and brine(20 mL), dried over Na₂SO₄ and filtered. The filtrate was evaporated invacuo and the residue was purified by flash column chromatography(EtOAc:Petrol ether=5:1) on silica gel to give(1-{3-[1-(6-methyl-quinolin-2-yl)-azetidin-3-yl]-pyrazin-2-yl}-piperidin-4-yl)-methanol(102 mg, 0.26 mmol 26%).

The following Table 32A lists compounds of Examples 28.1 to 28.18, whichwere made analogous to Scheme 28 by using the appropriate materials andreaction conditions, which are listed in Table 32B. The NMR data of theExamples are listed in Table 32C.

TABLE 32A EXAMPLES 28.1 TO 28.18 ESI-MS Ex. # Structure Chemical Name(M + 1) IC₅₀ (uM) 28.1

(1-{3-[1-(6-Methyl-quinolin- 2-yl)-azetidin-3-yl]-pyrazin-2-yl}-piperidin-4-yl)- methanol 390 0.00117 28.2

(1-{3-[1-(7-Fluoro-quinolin- 2-yl)-azetidin-3-yl]-pyrazin-2-yl}-piperidin-4-yl)- methanol 394 0.0001 28.3

(1-{3-[1-(6-Fluoro-quinolin- 2-yl)-azetidin-3-yl]-pyrazin-2-yl}-piperidin-4-yl)- methanol 394 0.0037 28.4

{1-[3-(1-[1,8]Naphthyridin- 2-yl-azetidin-3-yl)-pyrazin-2-yl]-piperidin-4-yl}- methanol 377 0.0419 28.5

(1-{3-[1-(6-Chloro-quinolin- 2-yl)-azetidin-3-yl]-pyrazin-2-yl}-piperidin-4-yl)- methanol 410 0.00116 28.6

(1-{3-[1-(6-Chloro- quinoxalin-2-yl)-azetidin-3-yl]-pyrdzin-2-yl}-piperidin- 4-yl)-methanol 411 0.0144 28.7

(1-{3-[1-(6-Methyl-pyridin- 2-yl)-azetidin-3-yl]-pyrazin-2-yl}-piperidin-4-yl)- methanol 340 0.217 28.8

(1-{3-[1-(5-Chloro-pyridin- 2-yl)-azetidin-3-yl]-pyrazin-2-yl}-piperidin-4-yl)- methanol 360 0.490 28.9

(1-(3-(1-(5-bromopyridin-2- yl)azetidin-3-yl)pyrazin-2-yl)piperidin-4-yl)methanol 404 0.466 28.10

(1-(3-(1-(8-methylquinolin- 2-yl)azetidin-3-yl)pyrazin-2-yl)piperidin-4-yl)methanol 390 0.446 28.11

(1-{3-[1-(8-Fluoro-quinolin- 2-yl)-azetidin-3-yl]-pyrazin-2-yl}-piperidin-4-yl)- methanol 394 0.00228 28.12

(1-(3-(1-(8-chloroquinolin-2- yl)azetidin-3-yl)pyrazin-2-yl)piperidin-4-yl)methanol 410 0.0233 28.13

(1-{3-[1-(8-Chloro- quinazolin-2-yl)-azetidin-3-yl]-pyrazin-2-yl}-piperidin- 4-yl)-methanol 411 0.0117 28.14

(1-{3-[1-(7-Chloro- quinazolin-2-yl)-azetidin-3-yl]-pyrazin-2-yl}-piperidin- 4-yl)-methanol 411 0.0001 28.15

(1-{3-[1-(6-Chloro- quinazolin-2-yl)-azetidin-3-yl]-pyrazin-2-yl}-piperidin- 4-yl)-methanol 411 0.0068 28.16

(1-{3-[1-(5-Chloro- quinazolin-2-yl)-azetidin-3-yl]-pyrazin-2-yl}-piperidin- 4-yl)-methanol 411 28.17

(1-{3-[1-(7-Chloro- quinoxalin-2-yl)-azetidin-3-yl]-pyrazin-2-yl}-piperidin- 4-yl)-methanol 411 0.0005 28.18

2-[3-(3-Piperidin-1-yl- pyrazin-2-yl)-azetidin-1-yl]- benzothiazole 352>10

TABLE 32B STARTING MATERIALS AND REACTION CONDITION FOR PREPARATION OFEXAMPLES 28.1 TO 28.18. Unless otherwise stated, all starting materialsare commercially available from common vendors. Ex. # Starting Material1 Starting Material 2 Reaction Condition 28.1

Cs₂CO₃, DMF, 100° C. 28.2 37 PREPARATION 11

Cs₂CO₃, DMF, 100° C. 28.3 37 PREPARATION 11

Cs₂CO₃, DMF, 100° C. 28.4 37 PREPARATION 11

Cs₂CO₃, DMF, 100° C. 28.5 37 PREPARATION 11

Cs₂CO₃, DMF, 100° C. 28.6 37 PREPARATION 11

Cs₂CO₃, DMF, 100° C. 28.7 37 PREPARATION 11

Cs₂CO₃, DMF, 100° C. 28.8 37 PREPARATION 11

Cs₂CO₃, DMF, 100° C. 28.9 37 PREPARATION 11

Cs₂CO₃, DMF, 100° C. 28.10 37 PREPARATION 11

Cs₂CO₃, DMF, 100° C. 28.11 37 PREPARATION 11

Cs₂CO₃, DMF, 100° C. 28.12 37 PREPARATION 11

Cs₂CO₃, DMF, 100° C. 28.13 37 PREPARATION 11

Cs₂CO₃, DMF, 100° C. 28.14 37 PREPARATION 11

Cs₂CO₃, DMF, 100° C. 28.15 37 PREPARATION 11

Cs₂CO₃, DMF, 100° C. 28.16 37 PREPARATION 11

Cs₂CO₃, DMF, 100° C. 28.17 37 PREPARATION 11

Cs₂CO₃, DMF, 100° C. 28.18

K₂CO₃, iPrOH/H₂O 160° C., μW

TABLE 32C 1H NMR δ (PPM) DATA FOR EXAMPLES 28.1 TO 28.18 Ex. # StructureNMR 28.1

(CDCl₃, 400 MHz): 8.14-8.06 (m, 2H); 7.79 (d, J = 8.8 Hz, 1H); 7.64 (d,J = 9.2 Hz, 1H); 7.37-7.35 (m, 2H); 6.62 (d, J = 9.2 Hz, 1H); 4.54-4.50(m, 2H); 4.45-4.41 (m, 2H); 4.33-4.25 (m, 1H); 3.58-3.56 (m, 2H); 3.45-3.42 (m, 2H); 2.88-2.81 (m, 2H); 2.43 (s, 3H); 1.89- 1.85 (m, 2H);1.75-1.65 (m, 1H); 1.50-1.46 (m, 2H). 28.2

(CDCl₃, 400 MHz): 8.10-8.09 (m, 1H); 8.03-8.02 (m, 1H); 7.77 (d, J = 8.8Hz, 1H); 7.51-7.47 (m, 1H); 7.30- 7.27 (m, 1H); 6.93-6.88 (m, 1H);6.54-6.51 (m, 1H); 4.50-4.46 (m, 2H); 4.41-4.37 (m, 2H); 4.28-4.23 (m,1H); 3.54-3.53 (m, 2H); 3.38 (d, J = 12.8 Hz, 2H); 1.85-1.82 (m, 2H);1.69-1.64 (m, 1H); 1.53-1.37 (m, 1H) 28.3

(CDCl₃, 400 MHz): 8.16-8.09 (m, 2H): 7.82 (d, J = 8.8 Hz, 1H); 7.73-7.69(m, 1H); 7.33-7.28 (m, 1H); 7.27- 7.23 (m, 1H); 6.69 (d, J = 8.8 Hz,1H); 4.56-4.52 (m, 2H); 4.46-4.43 (m, 2H); 4.36-4.30 (m, 1H); 3.60 (d, J= 6.4 Hz, 2H); 3.47-3.44 (m, 2H); 2.91-2.84 (m, 2H); 1.92-1.88 (m, 2H);1.75-1.69 (m, 1H); 1.53-1.43 (m, 2H). 28.4

(CD3OD, 400 MHz): 8.07 (s, 1H); 8.16-8.14 (m, 2H); 8.10 (d, J = 2.4 Hz,1H); 8.02 (d, J = 9.2 Hz, 1H); 7.26- 7.23 (m, 1H); 6.83 1(d, J = 9.2 Hz,1H); 4.55 (m, 2H); 4.37 (m, 3H); 3.50-3.43 (m, 4H); 2.89-2.83 (m, 2H);1.89-1.86 (m, 2H); 1.68-1.64 (m, 1H); 1.50-1.40(m, 2H). 28.5

(CDCl₃, 400 MHz): 8.18-8.10 (m, 2H); 7.80 (d, J = 4.8 Hz, 1H); 7.67 (d,J = 5.2 Hz, 1H); 7.59 (s, 1H); 7.49- 7.46 (m, 1H); 6.68 (d, J = 8.8 Hz,1H); 4.58-4.54 (m, 2H); 4.49-4.46 (m, 2H); 4.37-4.30 (m, 1H); 3.62 (d, J= 6.4 Hz, 2H); 3.46 (d, J = 12.8 Hz, 2H); 2.92-2.86 (m, 2H); 1.93-1.90(m, 2H); 1.76-1.69 (m, 1H); 1.54-1.44 (m, 2H). 28.6

(CDCl₃, 400 MHz): 8.20-8.13 (m, 2H); 8.13 (t, J = 2.4 Hz, 1H); 7.89 (d,J = 2.4 Hz, 1H); 7.65 (d, J = 8.8 Hz, 1H); 7.54-7.51 (m, 1H); 4.67-4.62(m, 2H); 4.59-4.55 (m, 2H); 4.44-4.37 (m, 1H); 3.61 (d, J = 6.0 Hz, 2H);3.46 (d, J = 12.8 Hz, 2H); 2.94-2.87(m, 2H); 1.94-1.91 (m, 2H);1.81-1.71 (m, 1H); 1.55-1.48 (m, 2H). 28.7

(CDCl₃, 400 MHz): 8.09 (s, 1H); 8.00 (s, 1H); 7.30- 7.26 (m, 1H);6.42-6.40 (m, 1H); 6.12-6.10 (m, 1H); 4.32(s, 2H); 4.21-4.20 (m, 3H);3.53-3.51 (m, 2H); 3.39-3.36 (m, 2H); 2.81-2.75 (m, 2H); 2.33 (s, 3H);1.82-1.79 (m, 2H); 1.65-1.63 (m, 1H); 1.45-1.34 (m, 2H); 1.18-1.17 (m,1H). 28.8

(CDCl₃, 400 MHz): 8.10-8.09 (m, 1H); 8.02-8.01 (m, 2H); 7.35-7.32 (m,1H); 6.24 (d, J = 8.8 Hz, 1H); 4.33- 4.29 (m, 2H); 4.25-4.19 (m, 3H);3.51 (d, J = 6.0 Hz, 2H); 3.35 (d, J = 12.4 Hz, 2H); 2.81-2.75 (m, 2H);1.83-1.80 (m, 2H); 1.70-1.59 (m, 1H); 1.43-1.36 (m, 2H). 28.9

(CDCl₃, 400 MHz): 8.16 (s, 2H); 8.08 (d, J = 3.2 Hz, 1H); 6.27 (d, J =8.8 Hz, 1H); 4.39-4.35 (m, 2H); 4.32- 4.27 (m, 3H); 3.58 (s, 2H);3.43-3.40 (m, 3H); 2.88- 2.82 (m, 2H); 2.05-2.00 (m, 1H); 1.89-1.86 (m,2H); 1.74-1.68 (m, 1H); 1.50-1.40 (m, 1H). 28.10

(CDCl₃, 400 MHz): 8.19-8.11 (m, 2H); 7.89 (d, J = 8.8 Hz, 1H); 7.49 (d,J = 8.0 Hz, 1H); 7.43 (d, J = 6.8, 1H); 7.15 (t, J = 7.6 Hz, 1H); 6.69(d, J = 8.8 Hz, 1H); 4.57- 4.53 (m, 2H); 4.47-4.43 (m, 2H); 4.38-4.31(m, 1H); 3.63-3.61 (m, 2H); 3.51-3.48 (m, 2H); 2.93-2.87 (m, 2H); 2.67(s, 3H); 1.94-1.91 (m, 2H); 1.82-1.62 (m, 1H); 1.55-1.45 (m, 2H). 28.11

(CDCl₃, 400 MHz): 8.09-8.02 (m, 2H); 7.82-7.83 (m, 1H); 7.32 (d, J = 8.0Hz, 1H); 7.21-7.16 (m, 1H); 7.07- 7.02 (m, 1H); 6.63 (d, J = 8.8 Hz,1H); 4.53-4.49 (m, 2H); 4.45-4.41 (m, 2H); 4.29-4.23 (m, 1H); 3.53 (d, J= 6.4 Hz, 2H); 3.39 (d, J = 12.8 Hz, 2H); 2.84-2.77 (m, 2H); 1.85-1.81(m, 2H); 1.68-1.64 (m, 1H). 1.63-1.36 (m, 2H) 28.12

(CDCl₃, 400 MHz): 8.09-8.02 (m, 2H); 7.80 (d, J = 8.8 Hz, 1H); 7.60-7.58(m, 1H); 7.44-7.43 (m, 1H); 7.04 (t, J = 7.6 Hz, 1H); 6.63 (d, J = 8.8Hz, 1H); 4.53-4.49 (m, 2H); 4.45-4.41 (m, 2H); 4.28-4.23 (m, 1H); 3.54(d, J = 6.4 Hz, 2H); 3.39 (d, J = 12.0 Hz, 2H); 2.81 (m, 2H); 1.86-1.83(m, 2H); 1.71-1.63 (m, 1H); 1.46-1.36 (m, 2H). 28.13

(CDCl₃, 400 MHz): 8.99 (s, 1H); 8.16-8.15 (m, 1H); 8.08-8.07 (m, 1H);7.76-7.74 (m, 1H); 7.58-7.56 (m, 1H); 7.13-7.09(m, 1H); 4.64-4.57 (m,4H); 4.31-4.27 (m, 1H); 3.58-3.55 (m, 2H); 3.45-3.41 (m, 2H); 2.88- 2.82(m, 2H); 2.33 (s, 1H); 1.89-1.86 (m, 2H); 1.73- 1.66 (m, 1H); 1.50-1.40(m, 2H) 28.14

(CDCl₃, 400 MHz): 8.91 (s, 1H); 8.10 (d, J = 2.8 Hz, 1H); 8.03 (d, J =2.8 Hz, 1H); 7.56-7.51 (m, 2H); 7.11- 7.09 (m, 1H); 4.57-4.52 (m, 2H);4.49-4.45 (m, 2H); 4.27-4.19 (m, 1H); 3.53 (d, J = 6.4 Hz, 2H); 3.38 (d,J = 12.4 Hz, 2H); 2.84-2.78 (m, 2H); 1.84-1.81 (m, 2H); 1.71-1.62 (m,1H); 1.47-1.43 (m, 2H) 28.15

(CDCl₃, 400 MHz): 8.96 (s, 1H); 8.18-8.09 (m, 2H); 7.66-7.58 (m, 3H);4.61-4.54 (m, 4H); 4.35-4.25 (m, 1H); 3.61-3.59 (m, 2H); 3.46-3.43 (m,2H); 2.92-2.85 (m, 2H); 1.91-1.89 (m, 2H); 1.75-1.71 (m, 1H); 1.52- 1.47(m, 2H). 28.16

(CDCl₃, 400 MHz): 9.42 (s, 1H); 8.20 (d, J = 2.8 Hz, 1H); 8.12 (d, J =2.4 Hz, 1H); 7.57-7.54 (m, 2H); 7.25- 7.23 (m, 1H); 4.67-4.63 (m, 2H);4.59-4.55 (m, 2H); 4.35-4.31 (m, 1H); 3.64-3.62 (m, 2H); 3.48-3.45 (m,2H); 2.93-2.86 (m, 2H); 193-1.90 (m, 2H); 1.78-1.72 (m, 1H);1.56-1.42(m, 3H). 28.17

(CDCl₃, 400 MHz): 8.14 (s, 1H); 8.12-8.11 (m, 1H); 8.06-8.05 (m, 1H);7.73 (d, J = 8.8 Hz, 1H); 7.63-7.62 (m, 1H); 7.26-7.24 (m, 1H);4.58-4.51 (m, 2H); 4.49- 4.47 (m, 2H); 4.36-4.28 (m, 1H); 3.54 (d, J =4.4 Hz, 2H); 3.38-3.35 (m, 2H); 2.86-2.79 (m, 2H); 1.85-1.83 (m, 2H);1.73-1.62 (m, 1H); 1.47-1.37 (m, 2H) 28.18

(CDCl₃, 400 MHz): 8.70-8.69 (m, 1 H); 8.42-8.41 (m, 1 H); 7.57-7.55 (m,1H); 7.47-7.45 (m, 1 H); 7.38-7.34 (m, 1 H); 7.26-7.22 (m, 1 H);5.21-5.18 (m, 1H); 4.72- 4.70 (m, 1 H)(; 4.30-4.16 (m, 2 H); 4.06-3.95(m, 3 H); 3.83-3.80 (m, 1 H); 3.46-3.41 (m, 1 H); 2.27-2.12 (m, 1 H);2.08-1.94 (m, 4 H); 1.61-1.58 (m, 1 H).

Example 29.12-{3-[3-(3-METHOXY-PHENYL)-PYRAZIN-2-YL]-AZETIDIN-1-YL}-8-METHYL-QUINOLINE

To a solution of 2-azetidin-3-yl-3-(3-methoxy-phenyl)-pyrazinehydrochloride (138 mg, 0.50 mmol) and 2-chloro-quinoline (84 mg, 0.50mmol) in DMF (6 mL) was added Cs₂CO₃ (325 mg, 1.0 mmol). The reactionmixture was stirred at 110° C. overnight. The reaction mixture wasdiluted with water, extracted with EtOAc (30 mL×2). The combined organicextracts were washed with water (30 mL) and brine (30 mL), dried overNa₂SO₄ and filtered. The filtrate was evaporated in vacuo and theresidue was purified by flash column chromatography on silica gel (20%to 40% EtOAc in petroleum ether) to give2-{3-[3-(3-methoxy-phenyl)-pyrazin-2-yl]-azetidin-1-yl}-8-methyl-quinoline(118 mg, 0.31 mmol, 63.35%).

The following Table 33A lists compounds of Examples 29.1 to 29.18, whichwere made analogous to Scheme 29 by using the appropriate materials andreaction conditions, which are listed in Table 33B. The NMR data of theExamples are listed in Table 33C.

TABLE 33A EXAMPLES 29.1 TO 29.18 ESI-MS IC₅₀ Ex. # Structure ChemicalName (M + 1) (uM) 29.1

2-(3-(3-(3-methoxyphenyl)pyrazin- 2-yl)azetidin-1-yl)-8- methylquinoline383 0.997 29.2

6-Chloro-2-{3-[3-(3-methoxy- phenyl)-pyrazin-2-yl]-azetidin-1-yl}-quinazoline 404 0.0750 29.3

8-Chloro-2-{3-[3-(3-methoxy- phenyl)-pyrazin-2-yl]-azetidin-1-yl}-quinoline 403 0.111 29.4

7-Fluoro-2-{3-[3-(3-methoxy- phenyl)-pyrazin-2-yl]-azetidin-1-yl}-quinoline 387 0.00122 29.5

2-{3-[3-(3-Methoxy-phenyl)- pyrazin-2-yl]-azetidin-1-yl}-6-methyl-quinoline 383 0.0061- 29.6

2-{3-[3-(3-Methoxy-phenyl)- pyrazin-2-yl]-azetidin-1-yl}-[1,8]naphthyridine 370 0.0794 29.7

8-Chloro-2-{3-[3-(3-methoxy- phenyl)-pyrazin-2-yl]-azetidin-1-yl}-quinazoline 404 29.8

5-Chloro-2-{3-[3-(3-methoxy- phenyl)-pyrazin-2-yl]-azetidin-1-yl}-quinazoline 404 29.9

2-(3-(3-(3-methoxyphenyl)pyrazin- 2-yl)azetidin-1-yl)-4-phenylpyrimidine 396 4.3 29.10

2-(3-(3-(3-methoxyphenyl)pyrazin- 2-yl)azetidin-1-yl)benzo[d]thiazole375 0.016 29.11

6-methoxy-2-(3-(3-(3- methoxyphenyl)pyrazin-2-yl)azetidin-1-yl)benzo[d]thiazole 405 0.010 29.12

2-(3-(3-(3-methoxyphenyl)pyrazin- 2-yl)azetidin-1-yl)-1,6- naphthyridine370 0.008 29.13

6-chloro-2-(3-(3-(3- methoxyphenyl)pyrazin-2- yl)azetidin-1-yl)quinoline403 0.0049 29.13

6-fluoro-2-(3-(3-(3- methoxyphenyl)pyrazin-2-yl)azetidin-1-yl)benzo[d]thiazole 393 0.029 29.14

2-(3-(3-(3-methoxyphenyl)pyrazin- 2-yl)azetidin-1-yl)quinoline-3-carbonitrile 394 0.0062 29.15

1-[3-(3-Phenyl-pyrazin-2-yl)- azetidin-1-yl]-phthalazine 340 1.910029.16

6-chloro-2-(3-(3-phenylpyrazin-2- yl)azetidin-1-yl)-1H-benzo[d]imidazole 362 0.0504 29.17

2-(3-(3-phenylpyrazin-2-yl)azetidin- 1-yl)-1H-benzo[d]imidazole 3270.191 29.18

2-((3-(3-phenylpyrazin-2- yl)azetidin-1-yl)methyl)-1H- benzo[d]imidazole342 1.07

TABLE 33B STARTING MATERIALS AND REACTION CONDITION FOR PREPARATION OFEXAMPLES 29.1 TO 29.18. Unless otherwise stated, all starting materialsare commercially available from common vendors. Ex. # Starting Material1 Starting Material 2 Reaction Condition 29.1

Cs₂CO₃, DMF, 100° C. 29.2 34 PREPARATION 10

Cs₂CO₃, DMF, 100° C. 29.3 34 PREPARATION 10

Cs₂CO₃, DMF, 100° C. 29.4 34 PREPARATION 10

Cs₂CO₃, DMF, 100° C. 29.5 34 PREPARATION 10

Cs₂CO₃, DMF, 100° C. 29.6 34 PREPARATION 10

Cs₂CO₃, DMF, 100° C. 29.7 34 PREPARATION 10

Cs₂CO₃, DMF, 100° C. 29.8 34 PREPARATION 10

Cs₂CO₃, DMF, 100° C. 29.9 34 PREPARATION 10

DMSO, 130-145° C., μW 29.10 34 PREPARATION 10

DMSO, 130-145° C., μW 29.11 34 PREPARATION 10

DMSO, 130-145° C., μW 29.12 34 PREPARATION 10

DMSO, 145-155° C., μW 29.13 34 PREPARATION 10

DMSO, 145-155° C., μW 29.13 34 PREPARATION 10

DMSO, 145-155° C., μW 29.14 34 PREPARATION 10

DMSO, 100° C., μW 29.15

Cs₂CO₃, DMF 120° C. 29.16

K₂CO₃, i-PrOH, H₂O, MW, 160° C. 29.17

K₂CO₃, i-PrOH, H₂O, MW, 160° C. 29.18

K₂CO₃, i-PrOH, H₂O, MW, 160° C.

TABLE 33C 1H NMR δ (PPM) DATA FOR EXAMPLES 29.1 TO 29.18 Ex. # StructureNMR 29.1

(CDCl₃, 400 MHz): 8.59-8.53 (m, 2H); 7.85 (d, J = 8.8 Hz, 1H); 7.47-7.40(m, 3H); 7.14- 7.10 (m, 1H); 7.08-7.03 (m, 3H); 6.62 (d, J = 8.8 Hz,1H); 4.44-4.37 (m, 5H); 3.90 (s, 3H); 2.64 (s, 3H). 29.2

(CDCl₃, 400 MHz): 9.07 (s, 1H); 8.60-8.59 (m, 2H); 7.88-7.86 (m, 1H);7.78-7.74 (m, 2H); 7.43-7.41 (m, 1H); 7.05-6.98 (m, 3H); 4.75-4.74 (m,4H); 4.45-4.43 (m, 1H); 3.87 (s, 3H). 29.3

(CDCl₃, 400 MHz): 8.61 (s, 1H); 8.56 (s, 1H); 7.87 (d, J = 8.8 Hz, 1H);7.67 (d, J = 7.6 Hz, 1H); 7.53 (d, J = 8.0 Hz, 1H); 7.48-7.44 (m, 1H);7.15-7.11 (m, 1H); 7.09-7.06 (m, 3H) 6.68 (d, J = 8.8 Hz, 1H); 4.55-4.42(m, 5H); 3.92 (s, 3H) 29.4

(CDCl₃, 400 MHz): 8.61-8.56 (m, 2H); 7.86- 7.83 (m, 1H); 7.59-7.55 (m,1H); 7.47-7.43 (m, 1H); 7.38-7.35 (m, 1H); 7.09-7.05 (m, 3H); 7.01-6.91(m, 1H); 6.58-6.65 (m, 1H); 4.48- 4.43 (m, 5H); 3.91 (s, 3H). 29.5

(CDCl₃, 400 MHz): 8.60-8.55 (m, 2H); 7.82 (d, J = 8.8 Hz, 1H); 7.71-7.69(m, 1H); 7.47- 7.43 (m, 1H); 7.41-7.39 (m, 2H); 7.09-7.04 (m, 3H); 6.62(d, J = 8.8 Hz, 1H); 4.49-4.43 (m, 5H); 3.91 (s, 3H); 2.46 (s, 3H). 29.6

(CDCl₃, 400 MHz): 8.59-8.54 (m, 2H); 7.77 (d, J = 8.8 Hz, 1H); 7.64 (d,J = 9.2 Hz, 1H); 7.57-7.56 (m, 1H); 7.47-7.41 (m, 2H); 7.07- 7.03 (m,3H); 6.62 (d, J = 8.8 Hz, 1H); 4.46- 4.40 (m, 5H); 3.89 (s, 3H). 29.7

(CDCl₃, 400 MHz): 9.00-8.99 (m, 1H); 8.61- 8.50 (m, 2H); 7.77-7.74 (m,1H); 7.59-7.56 (m, 1H); 7.43-7.40 (m, 1H); 7.14-7.10 (m, 1H); 7.07-7.01(m, 3H); 4.58-4.50 (m, 4H); 4.39- 4.36 (m, 1H); 3.87 (s, 3H). 29.8

(CDCl₃, 400 MHz): 9.54 (s, 1H); 8.65-8.63 (m, 2H); 7.83-7.80 (m, 2H);7.48-7.44 (m, 2H); 7.08-6.99 (m, 3H); 4.82-4.81 (m, 4H); 4.50-4.47 (m,1H); 3.89 (s, 3H). 29.9

(400 MHz, DMSO-d₆) 3.78-3.92 (m, 3H) 4.16-4.50 (m, 5H) 7.06-7.17 (m, 3H)7.26 (d, J = 5.09 Hz, 1H) 7.42-7.56 (m, 4H) 8.06- 8.16 (m, 2 H) 8.42 (d,J = 5.09 Hz, 1H) 8.64 (d, J = 2.15 Hz, 1H) 8.70 (d, J = 2.35 Hz, 1H).29.10

(400 MHz, DMSO-d₆) 3.84 (s, 3H) 4.24- 4.41 (m, 4H) 4.44-4.57 (m, 1H)7.01-7.17 (m, 4H) 7.24-7.33 (m, 1H) 7.42-7.52 (m, 2 H) 7.78 (d, J = 7.82Hz, 1H) 8.66 (d, J = 2.35 Hz, 1H) 8.72 (d, J = 2.35 Hz, 1H) 29.11

(400 MHz, DMSO-d₆) 3.71-3.79 (m, 3 H) 3.84 (s, 3 H) 4.21-4.35 (m, 4H)4.43-4.55 (m, 1H) 6.89 (dd, J = 8.80, 2.54 Hz, 1H) 7.04- 7.15 (m, 3H)7.34-7.43 (m, 2H) 7.44-7.51 (m, 1H) 8.65 (d, J = 2.35 Hz, 1H) 8.71 (d, J= 2.35 Hz, H) 29.12

(400 MHz, DMSO-d₆) 3.87 (s, 3H) 4.28-4.49 (m, 5H) 6.83 (d, J = 9.00 Hz,1H) 7.06-7.19 (m, 3 H) 7.38 (d, J = 5.87 Hz, 1H) 7.49 (t, J = 8.02 Hz,1H) 8.13 (d, J = 9.00 Hz, 1H) 8.42 (d, J = 5.67 Hz, 1H) 8.66 (d, J =2.35 Hz, 1H) 8.71 (d, J = 2.15 Hz, 1 H) 8.93 (s, 1H) 29.13

(400 MHz, DMSO-d₆) 8.69 (d, J = 2.35 Hz, 1H), 8.64 (d, J = 2.35 Hz, 1H),8.01 (d, J = 9.00 Hz, 1H), 7.82 (d, J = 2.15 Hz, 1H), 7.42- 7.60 (m,3H), 7.06-7.19 (m, 3H), 6.81 (d, J = 9.00 Hz, 1H), 4.36-4.47 (m, 1H),4.20-4.36 (m, 4H), 3.85 (s, 3H) 29.13

(400 MHz, DMSO-d₆) 8.71 (d, J = 2.54 Hz, 1H), 8.65 (d, J = 2.35 Hz, 1H),7.71 (dd, J = 2.74, 8.80 Hz, 1H), 7.41-7.49 (m, 2H), 7.05- 7.17 (m, 4H),4.49 (s, 1H), 4.23-4.38 (m, 4H), 3.83 (s, 3H) 29.14

(400 MHz, DMSO-d₆) 8.73 (s, 1H), 8.67 (d, J = 2.35 Hz, 1H), 8.61 (d, J =2.35 Hz, 1H), 7.77 (d, J = 8.02 Hz, 1H), 7.63-7.69 (m, 1H), 7.54-7.59(m, 1H), 7.41-7.47 (m, 1H), 7.30 (t, J = 7.43 Hz, 1H), 7.04-7.13 (m,3H), 4.43-4.55 (m, 4H), 4.33-4.42 (m, 1H), 3.81 (s, 3H) 29.15

(CD₃OD, 400 MHz): 8.84 (S, 1h); 8.65 (d, J = 2.4 Hz, 1H); 8.53 (d, J =2.4 Hz, 1H); 8.03- 8.00 (m, 1H); 7.92-7.80 (m, 3H); 7.57-7.50 (m, 5H);4.77-4.71 (m, 4H); 4.49-4.46 (m, 1H). 29.16

(CDCl₃, 400 MHz): 8.54-8.53 (m, 1H); 8.42 (s, 1H); 7.54-7.53 (m, 3H);7.35-7.32 (m, 2H); 7.26-7.20 (m, 1H); 7.11-7.09 (m, 1H); 6.97- 6.95 (m,1H); 4.46-4.42 (m, 2H); 4.18-4.15 (m, 2H); 4.03-4.00 (m, 1H). 29.17

(MeOD, 400 MHz): 8.66-8.65 (m, 1H); 8.55- 8.54 (m, 1H); 7.58-7.52 (m,5H); 7.22-7.19 (m, 2H); 7.01-6.98 (m, 2H); 4.51-4.45 (m, 1H), 4.38-4.30(m, 4H). 29.18

(MeOD, 400 MHz): 8.67-8.65 (m, 1H); 8.60- 8.58 (m, 1H); 7.67-7.63 (m,2H); 7.55-7.47 (m, 5H); 7.39-7.36 (m, 2H); 4.81 (s, 2H); 4.55- 4.48 (m,5H).

Example 30.1 3-(3-(1-(QUINOLIN-2-YL)AZETIDIN-3-YL)PYRAZIN-2-YL)BENZAMIDE

A mixture of3-(3-(1-(quinolin-2-yl)azetidin-3-yl)pyrazin-2-yl)benzonitrile (0.072 g,0.198 mmol), potassium hydroxide (0.111 g, 1.981 mmol, v/w) and t-BuOH(2 mL, Acros) was heated at 80° C. overnight. LCMS showed the product.The mixture was diluted with water and extracted with a mixture ofCHCl₃:i-PrOH (3:1) three times. The combined organic layers were driedover Na₂SO₄ and concentrated in vacuo. The product was obtained as awhite solid (75 mg, 99%).

The following Table 34A lists compounds of Examples 30.1 to 30.4, whichwere made analogous to Scheme 30 by using the appropriate materials andreaction conditions, which are listed in Table 34B. The NMR data of theExamples are listed in Table 34C.

TABLE 34A EXAMPLES 30.1 TO 30.4 ESI-MS Ex. # Structure Chemical Name(M + 1) IC₅₀ (μM) 30.1

3-(3-(1-(quinolin-2- yl)azetidin-3-yl)pyrazin-2- yl)benzamide 382 0.000830.2

4-(3-(1-(quinolin-2- yl)azetidin-3-yl)pyrazin-2 yl)benzamide 382 0.001330.3

2-fluoro-5-(3-(1-(quinolin-2- yl)azetidin-3-yl)pyrazin-2- yl)benzamide400 0.0006 30.4

2-fluoro-4-(3-(1-(quinolin-2- yl)azetidin-3-yl)pyrazin-2- yl)benzamide400 0.002

TABLE 34B STARTING MATERIALS AND REACTION CONDITION FOR PREPARATION OFEXAMPLES 30.1 TO 30.4. Unless otherwise stated, all starting materialsare commercially available from common vendors. Reaction Ex. # Keystarting Material(s)/Source Condition 30.1

KOH, t-BuOH, 80° C. 30.2

KOH, t-BuOH, 80° C. 30.3

EtOH/DMSO NaOH/H₂O₂ 30.4

EtOH/DMSO NaOH/H₂O₂

TABLE 34C 1H NMR δ (PPM) DATA FOR EXAMPLES 30.1 TO 30.4 Ex # Structure¹H NMR 30.1

(400 MHz, DMSO-d₆) 4.24-4.35 (m, 4 H) 4.37-4.46 (m, 1 H) 6.75 (d, J =8.80 Hz, 1 H) 7.21 (t, J = 7.34 Hz, 1 H) 7.45-7.59 (m, 3 H) 7.62-7.81(m, 3 H) 7.99-8.17 (m, 4 H) 8.67 (d, J = 2.35 Hz, 1 H) 8.71 (d, J = 2.35Hz, 1 H) 30.2

(400 MHz, DMSO-d₆) 4.20-4.35 (m, 4 H) 4.38-4.49 (m, 1 H) 6.75 (d, J =9.00 Hz, 1 H) 7.16-7.28 (m, 1 H) 7.45-7.59 (m, 3 H) 7.64- 7.74 (m, 3 H)7.98-8.20 (m, 4 H) 8.66 (d, J = 2.35 Hz, 1 H) 8.71 (d, J = 2.35 Hz, 1 H)30.3

(400 MHz, chloroform-d) 4.34-4.51 (m, 5 H) 5.94 (br. s., 1 H) 6.64 (d, J= 9.00 Hz, 1 H) 6.77 (d, J = 10.17 Hz, 1 H) 7.19-7.25 (m, 1 H) 7.34 (dd,J = 11.35, 8.61 Hz, 1 H) 7.49-7.56 (m, 1 H) 7.60 (d, J = 7.82 Hz, 1 H)7.72 (d, J = 8.41 Hz, 1 H) 7.77 (ddd, J = 8.17, 5.14, 2.54 Hz, 1 H) 7.88(d, J = 8.80 Hz, 1 H) 8.30 (dd, J = 7.43, 2.54 Hz, 1 H) 8.55 (d, J =2.35 Hz, 1 H) 8.62 (d, J = 2.35 Hz, 1 H). 30.4

(400 MHz, chloroform-d) 4.33-4.52 (m, 5 H) 5.89 (br. s., 1 H) 6.64 (d, J= 9.00 Hz, 1 H) 6.76 (d, J = 11.35 Hz, 1 H) 7.20-7.26 (m, 1 H) 7.36-7.47 (m, 2 H) 7.54 (t, J = 7.73 Hz, 1 H) 7.61 (d, J = 8.02 Hz, 1 H) 7.73(d, J = 8.41 Hz, 1 H) 7.89 (d, J = 9.00 Hz, 1 H) 8.30 (t, J = 8.02 Hz, 1H) 8.58 (d, J = 2.35 Hz, 1 H) 8.65 (d, J = 2.35 Hz, 1 H).

Example 31.12-(3-(3-(1-(QUINOLIN-2-YL)AZETIDIN-3-YL)PYRAZIN-2-YL)PHENYL)PROPAN-2-OL

To a mixture of methyl3-(3-(1-(quinolin-2-yl)azetidin-3-yl)pyrazin-2-yl)benzoate (0.044 g,0.110 mmol) and THF (1 mL) was added methylmagnesium bromide (0.110 mL,0.331 mmol). The mixture was stirred at RT for 2 h. LCMS showed theproduct. The mixture was diluted with saturated NH₄Cl and extracted withEtOAc. The organic layer was dried over Na₂SO₄ and concentrated invacuo. The crude was purified by silica gel chromatography (12 g,10%-100% EtOAc-Hexane). The product was obtained as a white solid (44mg, 100%). ¹H NMR (400 MHz, chloroform-d) δ ppm 1.66 (s, 6H) 1.88 (br.s., 1H) 4.29-4.63 (m, 5H) 6.62 (d, J=8.80 Hz, 1H) 7.22 (t, J=7.43 Hz,1H) 7.39 (d, J=7.63 Hz, 1H) 7.51 (dt, J=11.79, 7.70 Hz, 2 H) 7.57-7.65(m, 2H) 7.66-7.76 (m, 2H) 7.87 (d, J=8.80 Hz, 1H) 8.54 (d, J=2.35 Hz,1H) 8.58 (d, J=2.15 Hz, 1H). ESI (M+1) 397; calc for C₂₅H₂₄N₄ 396.

The following Table 35A lists compounds of Examples 31.1 to 31.2, whichwere made analogous to Scheme 31 by using the appropriate materials andreaction conditions, which are listed in Table 35B. The NMR data of theExamples are listed in Table 35C.

TABLE 35A EXAMPLES 31.1 TO 31.2 ESI-MS Ex. # Structure Chemical Name(M + 1) IC₅₀ (μM) 31.1

2-(3-(3-(1-(quinolin-2- yl)azetidin-3-yl)pyrazin-2-yl)phenyl)propan-2-ol 397 0.0034 31.2

2-(4-(3-(1-(quinolin-2- yl)azetidin-3-yl)pyrazin-2-yl)phenyl)propan-2-ol 397 0.0042

TABLE 35B STARTING MATERIALS AND REACTION CONDITION FOR PREPARATION OFEXAMPLES 31.1 TO 31.2. Unless otherwise stated, all starting materialsare commercially available from common vendors. Ex. # Key StartingMaterial(s)/Source Reaction Condition 31.1

CH₃MgBr, THF, RT 31.2

CH₃MgBr, THF, RT

TABLE 35C 1H NMR δ (PPM) DATA FOR EXAMPLES 31.1 TO 31.2 Ex # StructureNMR 31.1

(400 MHz, chloroform-d) 1.66 (s, 6 H) 1.88 (br. s., 1 H) 4.29-4.63 (m, 5H) 6.62 (d, J = 8.80 Hz, 1 H) 7.22 (t, J = 7.43 Hz, 1 H) 7.39 (d, J =7.63 Hz, 1 H) 7.51 (dt, J = 11.79, 7.70 Hz, 2 H) 7.57-7.65 (m, 2 H)7.66-7.76 (m, 2 H) 7.87 (d, J = 8.80 Hz, 1 H) 8.54 (d, J = 2.35 Hz, 1 H)8.58 (d, J = 2.15 Hz, 1 H). 31.2

(400 MHz, chloroform-d) 1.65 (s, 6 H) 1.80 (s, 1 H) 4.38-4.53 (m, 5 H)6.63 (d, J = 8.80 Hz, 1 H) 7.22 (t, J = 7.43 Hz, 1 H) 7.47-7.56 (m, 3 H)7.60 (d, J = 7.63 Hz, 1 H) 7.65 (d, J = 8.41 Hz, 2 H) 7.72 (d, J = 8.41Hz, 1 H) 7.87 (d, J = 9.00 Hz, 1 H) 8.53 (d, J = 2.35 Hz, 1 H) 8.57 (d,J = 2.54 Hz, 1 H).

Example 32.12-(3-(3-(1,2,3,6-TETRAHYDROPYRIDIN-4-YL)PYRAZIN-2-YL)AZETIDIN-1-YL)QUINOLINE

A mixture of tert-butyl4-(3-(1-(quinolin-2-yl)azetidin-3-yl)pyrazin-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate(0.100 g, 0.225 mmol, SCHEME 5) CH₂Cl₂ (1 mL) and TFA (0.174 mL, 2.255mmol) was stirred at RT for 1 h. LCMS showed the product and no morestarting material was present. The mixture was concentrated in vacuo andneutralized with Na₂CO₃. The mixture was extracted with a mixture ofCHCl₃:i-PrOH (3:1) three times. The organic layer was dried over Na₂SO₄and concentrated in vacuo. The product was obtained as a white solid (77mg, 99%).

ESI-MS (M+1): 344. PDE10 IC₅₀ (μM): 0.013.

¹H NMR δ (ppm): (400 MHz, chloroform-d) 2.53 (d, J=1.76 Hz, 2H) 3.18 (t,J=5.67 Hz, 2H) 3.61 (d, J=2.74 Hz, 2H) 4.38-4.59 (m, 5H) 5.86 (br. s.,1H) 6.66 (d, J=8.80 Hz, 1H) 7.22 (t, J=7.43 Hz, 1H) 7.49-7.57 (m, 1H)7.61 (d, J=7.83 Hz, 1H) 7.74 (d, J=8.41 Hz, 1H) 7.89 (d, J=9.00 Hz, 1H)8.42 (d, J=2.35 Hz, 1H) 8.47 (d, J=2.35 Hz, 1H).

Example 33.1 LITHIUM3-(3-(1-(QUINOLIN-2-YL)AZETIDIN-3-YL)PYRAZIN-2-YL)BENZOATE

A mixture of methyl3-(3-(1-(quinolin-2-yl)azetidin-3-yl)pyrazin-2-yl)benzoate (0.079 g,0.198 mmol, SCHEME 5), lithium hydroxide hydrate (0.017 g, 0.397 mmol),water (0.4 mL) and THF (1.2 mL) was stirred at RT overnight. The mixturewas concentrated in vacuo. The product was obtained as an off-whitesolid (83 mg, 108%).

ESI-MS (M+1): 383. PDE10 IC₅₀ (μM): 0.0016.

¹H NMR δ (ppm): (400 MHz, DMSO-d₆) 4.20-4.45 (m, 5H) 6.76 (d, J=9.00 Hz,1H) 7.21 (t, J=7.04 Hz, 1H) 7.42-7.61 (m, 4H) 7.70 (d, J=7.82 Hz, 1H)7.97-8.04 (m, 2H) 8.08 (s, 1H) 8.64 (dd, J=9.39, 2.35 Hz, 2H).

Example 34.1(1H-BENZOIMIDAZOL-2-YL)-{3-[3-(2-METHOXY-PHENOXY)-PYRAZIN-2-YL]-AZETIDIN-1-YL}-METHANONE

The mixture of 2-azetidin-3-yl-3-(2-methoxy-phenoxy)-pyrazinehydrochloride (108 mg, 0.37 mmol), HATU (280 mg, 0.74 mmol) and TEA (130mg, 1.3 mmol) in dry DCM (10 mL) was stirred at RT for 30 min, then1H-benzoimidazole-2-carboxylic acid was added to the solution. Thesolution was heated to 80° C. overnight. The mixture was poured intosaturated aqueous Na₂CO₃ and extracted with DCM (50 mL×2). The organiclayer was washed with brine, dried over Na₂SO₄ and concentrated to givethe crude compound, which was purified by ISCO silica gel column (10% to80% EtOAc in petroleum ether) and followed by reverse phase prep. HPLC(10% to 80% water/MeCN) to give(1H-benzoimidazol-2-yl)-{3-[3-(2-methoxy-phenoxy)-pyrazin-2-yl]-azetidin-1-yl}-methanone(40 mg, 0.11 mmol, yield 27%).

The following Table 36A lists compounds of Examples 34.1 to 34.2, whichwere made analogous to Scheme 34 by using the appropriate materials andreaction conditions, which are listed in Table 36B. The NMR data of theExamples are listed in Table 36C.

TABLE 36A EXAMPLES 34.1 TO 34.2 ESI-MS IC₅₀ Ex. # Structure ChemicalName (M + 1) (uM) 34.1

(1H-Benzoimidazol-2-yl)-{3-[3- (2-methoxy-phenoxy)-pyrazin-2-yl]-azetidin-1-yl}-methanone 402 1.74 34.2

(1H-Benzoimidazol-2-yl)-{3-[3- (3-methoxy-phenoxy)-pyrazin-2-yl]-azetidin-1-yl}-methanone 402 0.78 34.3

(1H-benzoimidazol-2-yl)-{3-[3- (4-methoxy-phenoxy)-pyrazin-2-yl]-azetidin-1-yl}-methanone 402 2.04 34.4

(1H-Benzoimidazol-2-yl)-[3-(3- phenoxy-pyrazin-2-yl)-azetidin-1-yl]-methanone 372 0.73 34.5

(1H-benzoimidazol-2-yl)-{3-[3- (tetrahydro-pyran-4-yl)-pyrazin-2-yl]-azetidin-1-yl}-methanone 364 0.124 34.6

(7-Chloro-1H-benzoimidazol-2- yl)-[3-(3-phenyl-pyrazin-2-yl)-azetidin-1-yl]-methanone 390 0.131 34.7

(6-Chloro-1H-benzoimidazol-2- yl)-[3-(3-phenyl-pyrazin-2-yl)-azetidin-1-yl]-methanone 390 0.0692 34.8

(7-Fluoro-1H-benzoimidazol-2- yl)-[3-(3-phenyl-pyrazin-2-yl)-azetidin-1-yl]-methanone 374 0.0438 34.9

(6-Fluoro-1H-benzoimidazol-2- yl)-[3-(3-phenyl-pyrazin-2-yl)-azetidin-1-yl]-methanone 374 0.0373 34.10

(6-methyl-1H-benzoimidazol-2- yl)-[3-(3-phenyl-pyrazin-2-yl)-azetidin-1-yl]-methanone 370 0.0687 34.11

(6-methyl-1H-benzoimidazol-2- yl)-[3-(3-phenyl-pyrazin-2-yl)-azetidin-1-yl]-methanone 370 0.0219 34.12

(1H-benzoimidazol-2-yl)-{3-[3-(2- methoxy-phenyl)-pyrazin-2-yl]-azetidin-1-yl}-methanone 386 0.0978 34.13

(1H-benzoimidazol-2-yl)-{3-[3-(3- methoxy-phenyl)-pyrazin-2-yl]-azetidin-1-yl}-methanone 386 0.087 34.14

(1H-Benzoimidazol-2-yl)-{3-[3- (4-methoxy-phenyl)-pyrazin-2-yl]-azetidin-1-yl}-methanone 386 0.0322 34.14

(1H-benzoimidazol-2-yl)-[3-(2- phenyl-pyridin-3-yl)-azetidin-1-yl]-methanone 355 0.515

TABLE 36B STARTING MATERIALS AND REACTION CONDITION FOR PREPARATION OFEXAMPLES 34.1 TO 34.2. Unless otherwise stated, all starting materialsare commercially available from common vendors. Ex. # Starting Material1 Starting Material 2 Reaction Condition 34.1

HATU, TEA, DCM, 80° C. 34.2

HATU, TEA, DCM, 80° C. 34.3

HATU, TEA, DCM, 80° C. 34.4

HATU, TEA, DCM, 80° C. 34.5

HATU, TEA, THF 34.6

HATU, TEA, DCM, 0° C. to RT 34.7

HATU, TEA, DCM, 0° C. to RT 34.8

HATU, TEA, DCM, 0° C. to RT 34.9

HATU, TEA, DCM, 0° C. to RT 34.10

HATU, TEA, DCM, 0° C. to RT 34.11

HATU, TEA, DCM, 0° C. to RT 34.12

HATU, TEA, DCM, RT 34.13

HATU, TEA, DCM, RT 34.14

HATU, TEA, DCM, RT 34.14

HATU, TEA, DCM, RT

TABLE 36C 1H NMR δ (PPM) DATA FOR EXAMPLES 34.1 TO 34.22 Ex # StructureNMR 34.1 

(CD₃OD, 400 MHz): 8.19 (d, J = 2.4 Hz, 1H); 7.93 (d, J = 2.8 Hz, 1H);7.74-7.70 (m, 2H); 7.37- 7.33 (m, 2H); 7.26-7.15 (m, 1H); 7.02-6.97 (m,3H); 5.38- 5.29 (m, 2H); 4.85-4.71 (m, 2H); 4.53-4.10 (m, 1H); 3.69 (s,3H). 34.2 

(CD₃OD, 400 MHz): 8.18 (d, J = 2.4 Hz, 1H); 7.95 (d, J = 2.8 Hz, 1H);7.70- 7.68 (m, 2H); 7.35-7.33 (m, 2H); 7.28-7.24 (m, 1H); 6.76- 6.73 (m,1H); 6.66-6.64 (m, 2H); 5.32-5.27 (m, 1H); 5.21- 5.17 (m, 1H); 4.36-4.63(m, 2H); 4.49-4.43 (m, 1H); 3.74 (s, 3H). 34.3 

(CD₃OD, 400 MHz): 8.27-8.26 (m, 1H); 7.99- 7.98 (m, 1H); 7.85-7.83 (m,2H); 7.67-7.64 (m, 2H); 7.08- 7.06 (m, 2H); 6.96-6.94 (m, 2H); 5.15-5.13(m, 2H); 4.76- 7.74 (m, 2H); 4.56-4.53 (m, 1H); 3.79 (s, 3H). 34.4 

(CD₃OD, 400 MHz): 8.29 (d, J = 2.8 Hz, 1H); 8.00-7.99 (m, 1H); 7.75-7.73(m, 2H); 7.49- 7.47 (m, 2H); 7.43-7.39 (m, 2H); 7.25-7.23 (m, 1H); 7.17-7.14 (m, 2H); 5.22-5.13 (m, 2H); 4.73-4.68 (m, 2H); 4.58- 4.51 (m, 1H)34.5 

(CD₃OD, 400 MHz): 8.48-8.45 (m, 2H); 7.74- 7.72 (m, 2H); 7.47-7.44 (m,2H); 5.15-5.12 (m, 1H); 5.03- 5.01 (m, 1H); 4.64-4.56 (m, 3H); 4.09-4.02(m, 2H); 3.65- 3.59 (m, 2H); 3.17-3.13 (m, 1H); 2.05-2.03 (m, 2H); 1.66-1.63 (m, 2H) 34.6 

(CDCl₃, 400 MHz) 8.62-8.58 (m, 2H); 7.54- 7.49 (m, 6H); 7.31-7.20 (m,2H); 5.16 (br, 2H); 4.63- 4.59 (m, 1H); 4.50-4.46 (m, 1H); 4.40-4.33 (m,1H). 34.7 

(CDCl₃, 400 MHz): 8.55- 8.51 (m, 2H); 7.47-7.41 (m, 7H); 7.24 (s, 1H);5.06 (m, 2H); 4.53- 4.50 (m, 1H); 4.42-4.37 (m, 1H); 4.30- 4.28 (m, 1H).34.8 

(CDCl₃, 400 MHz): 8.68- 8.59 (m, 2H); 7.62-7.49 (m, 5H); 7.45-7.41 (m,1H); 7.38-7.20 (m, 1H); 7.05-6.96 (m, 1H); 5.25- 5.14 (m, 2H); 4.64-4.60(m, 1H); 4.52-4.49 (m, 1H); 4.47- 4.33 (m, 1H). 34.9 

(MeOD, 400 MHz): 8.62- 8.61 (m, 1H); 8.55-8.54 (m, 1H); 7.68-7.52 (m,6H); 7.35- 7.31 (m, 1H); 7.11-7.08 (m, 1H); 5.06- 5.00 (m, 2H);4.46-4.36 (m, 3H). 34.10

(CDCl₃, 400 MHz): 8.64- 8.63 (m, 1H); 8.61-8.60 (m, 1H); 7.56-7.52 (m,4H); 7.47- 7.45 (m, 2H); 7.28-7.26 (m, 1H); 7.17-7.15 (m, 1H); 5.17-5.10 (m, 2H); 4.56-4.54 (m, 1H); 4.41-4.36 (m, 2H); 2.59 (s, 3H). 34.11

(CDCl₃, 400 MHz): 8.54- 8.53 (m, 1H); 8.51-8.50 (m, 1H); 7.45-7.43 (m,6H); 7.18 (brs, 1H); 7.06-7.04 (m, 1H); 5.10- 5.06 (m, 2H); 4.55-4.53(m, 1H); 4.43- 4.38 (m, 1H); 4.29-4.27 (m, 1H); 2.14 (s, 3H). 34.12

(CDCl₃, 400 MHz): 8.69- 8.68 (m, 1H); 8.56-8.55 (m, 1H); 7.74-7.72 (m,2H); 7.53-7.45 (m, 3H); 7.36-7.34 (m, 1H); 7.17- 7.12(m, 2H); 5.01-4.95(m, 2H); 4.50-4.91 (m, 2H); 4.15- 4.09 (m, 1H); 3.81 (s, 3H). 34.13

(CDCl₃, 400 MHz): 8.62- 8.57 (m, 2H); 7.69-7.67 (m, 2H); 7.46-7.42 (m,1H); 7.34- 7.32 (m, 2H); 7.06-7.01 (m, 3H); 5.19-5.15 (m, 2H); 4.68-4.31 (m, 3H); 3.88 (s, 3H). 34.14

(CDCl₃, 400 MHz): 8.86 (d, J = 2.8 Hz, 2H); 7.73-7.71 (m, 2H); 7.45-7.43 (m, 2H); 7.40-7.37 (m, 2H); 7.07-7.05 (m, 2H); 5.24- 5.22 (m, 1H);5.13-5.12 (m, 1H); 4.59-4.57 (m, 1H); 4.48- 4.40 (m, 2H); 3.89 (s, 3H).34.14

(CDCl₃, 400 MHz): 8.87- 8.86 (m, 1H); 8.58-8.56 (m, 1H); 7.86-7.81 (m,1H); 7.70- 7.68 (m, 2H); 7.58-7.56 (m, 3H); 7.45-7.38 (m, 4H); 5.17-5.15 (m, 1H); 4.98-4.96 (m, 1H); 4.51-4.47 (m, 1H); 4.28- 4.15 (m, 2H).

Example 35.12-(3-(3-(1H-INDOL-5-YL)PYRAZIN-2-YL)AZETIDIN-1-YL)QUINAZOLINE

The above example was run in four different flasks under four differentsets of reaction conditions. All four flasks were then combined beforework up and purified to give the product.

Reaction condition (1): 2M aqueous sodium carbonate (0.252 mL, 0.504mmol, J. T. Baker) was added to a stirred mixture of2-(3-(3-chloropyrazin-2-yl)azetidin-1-yl)quinazoline (0.050 g, 0.168mmol, Preparation 1), indole-5-boronic acid (0.032 g, 0.202 mmol,Frontier Scientific), and trans-dichlorobis(triphenylphosphine)palladium(ii) (0.006 mg, 0.008 mmol, Strem) in 1,4-dioxane (0.7 mL) in a sealedtube under an argon atmosphere. The reaction mixture was stirred at 80°C. for 17 h before being cooled to RT and combined with the other threecrude reactions.

Reaction condition (2) 2M aqueous sodium carbonate (0.252 mL, 0.504mmol, J. T. Baker) was added to a stirred mixture of2-(3-(3-chloropyrazin-2-yl)azetidin-1-yl)quinazoline (0.050 g, 0.168mmol, Preparation 1), indole-5-boronic acid (0.032 g, 0.202 mmol,Frontier), and tetrakis(triphenylphosphine)palladium (0.010 g, 0.008mmol, Strem) in 1,4-dioxane (0.7 mL) in a sealed tube under an argonatmosphere. The reaction mixture was stirred at 80° C. for 17 h beforebeing cooled to RT and combined with the other three crude reactions.

Reaction condition (3)2-(3-(3-Chloropyrazin-2-yl)azetidin-1-yl)quinazoline

(0.050 g, 0.168 mmol, Preparation 1), indole-5-boronic acid (0.032 g,0.202 mmol, Frontier Scientific), dichloro 1,1′-bis(diphenylphosphino)ferrocene palladium (ii) (0.007 g, 0.008 mmol, Strem), and potassiumphosphate (0.035 mL, 0.420 mmol, Aldrich) were mixed in 1,4-dioxane (1.5mL) and water (0.3 mL) in a sealed tube under an argon atmosphere. Thereaction mixture was stirred at 80° C. for 17 h before being cooled toRT and combined with the other three crude reactions

Reaction condition (4)2-(3-(3-Chloropyrazin-2-yl)azetidin-1-yl)quinazoline (0.050 g, 0.168mmol, Preparation 1), indole-5-boronic acid (0.032 g, 0.202 mmol,Frontier Scientific),bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium (ii)(0.006 g, 0.008 mmol, Strem), and potassium phosphate (0.089 g, 0.420mmol, Aldrich) were mixed in 1,4-dioxane (0.8 mL) and water (0.2 mL) ina sealed tube under an argon atmosphere. The reaction mixture wasstirred at 80° C. for 17 h before being cooled to RT and combined withthe other three crude reactions.

The combined reaction mixtures were diluted with water and extractedwith DCM (1×). The organic extract was dried over magnesium sulfate,filtered, and concentrated in vacuo. The resulting crude material waspurified via silica gel flash column chromatography eluting with 0% to100% EtOAc in hexanes to give 0.217 g (85%) of a yellow amorphous solid.

ESI-MS (M+1): 379.1. PDE10 IC₅₀ (μM): 0.009.

¹H NMR δ (ppm): (400 MHz, d-chloroform) 4.44-4.60 (m, 5H) 6.63 (s, 1H)7.22 (t, J=7.20 Hz, 1H) 7.30 (d, J=2.00 Hz, 1H) 7.35 (d, J=8.41 Hz, 1H)7.50 (d, J=8.41 Hz, 1H) 7.59-7.70 (m, 3H) 7.77 (s, 1H) 8.47-8.57 (m, 3H)9.01 (s, 1H).

The following Table 37 lists compounds of Examples 36.1 to 36.190, whichcan be made according to the above schemes and preparations.

TABLE 37 Examples 36.1 to 36.190 Ex. # Structure Chemical Name 36.1

2-(3-(5-(2-methoxypyridin-3- yl)pyrimidin-4-yl)azetidin-1-yl)quinazoline 36.2

2-(3-(6-(2-methoxypyridin-3- yl)-1H-imidazo[4,5-b]pyrazin-5-yl)azetidin-1-yl)quinazoline 36.3

2-(2-methoxypyridin-3-yl)-3-(1- (quinazolin-2-yl)azetidin-3-yl)pyrido[2,3-b]pyrazine 36.4

3-(2-methoxypyridin-3-yl)-2-(1- (quinazolin-2-yl)azetidin-3-yl)pyrido[2,3-b]pyrazine 36.5

2-(3-(3-(2-methoxypyridin-3- yl)quinoxalin-2-yl)azetidin-1-yl)quinazoline 36.6

methyl 3-(3-(3-hydroxy-1-(quinazolin- 2-yl)azetidin-3-yl)pyrazin-2-yl)benzoate 36.7

methyl 3-(3-(3-hydroxy-1-(quinolin-2-yl)azetidin-3-yl)pyrazin-2-yl)benzoate 36.8

3-(3-(4-(methylsulfonyl)piperidin-1- yl)pyrazin-2-yl)-1-(quinazolin-2-yl)azetidin-3-ol 36.9

3-(3-(4-(hydroxymethyl)piperidin-1- yl)pyrazin-2-yl)-1-(quinolin-2-yl)azetidin-3-ol 36.10

1-(3-(3-hydroxy-1-(quinolin-2- yl)azetidin-3-yl)pyrazin-2-yl)piperidine-4-carbonitrile 36.11

3-(3-(4-(methylsulfonyl)piperidin-1- yl)pyrazin-2-yl)-1-(quinolin-2-yl)azetidin-3-ol 36.12

methyl 3-(3-(3-fluoro-1-(quinolin- 2-yl)azetidin-3-yl)pyrazin-2-yl)benzoate 36.13

methyl 3-(3-(3-fluoro-1-(quinazolin- 2-yl)azetidin-3-yl)pyrazin-2-yl)benzoate 36.14

2-(3-fluoro-3-(3-(4- (methylsulfonyl)piperidin-1-yl)pyrazin-2-yl)azetidin-1-yl)quinoline 36.15

(1-(3-(3-fluoro-1-(quinazolin-2- yl)azetidin-3-yl)pyrazin-2-yl)piperidin-4-yl)methanol 36.16

1-(3-(3-fluoro-1-(quinazolin-2- yl)azetidin-3-yl)pyrazin-2-yl)piperidine-4-carbonitrile 36.17

2-(3-fluoro-3-(3-(4- (methylsulfonyl)piperidin-1-yl)pyrazin-2-yl)azetidin-1- yl)quinazoline 36.18

3-(3-(4-(hydroxymethyl)piperidin- 1-yl)pyrazin-2-yl)-1-(quinazolin-2-yl)azetidin-3-ol 36.19

1-(3-(1-hydroxy-3-(quinazolin-2- yl)cyclobutyl)pyrazin-2-yl)piperidine-4-carbonitrile 36.20

2-(3-(6-(3- methoxyphenyl)pyrazolo[1,5-a]pyridin-7-yl)azetidin-1-yl)quinoline 36.21

2-(3-(7-(3- methoxyphenyl)imidazo[1,5-a]pyridin-8-yl)azetidin-1-yl)quinoline 36.22

2-(3-(6-(3- methoxyphenyl)pyrazolo[1,5-a]pyrazin-7-yl)azetidin-1-yl)quinoline 36.23

2-(3-(6-(1H-imidazol-4-yl)-3-(3- methoxyphenyl)pyrazin-2-yl)azetidin-1-yl)quinoline 36.24

2-(3-(3-(3- methoxyphenyl)pyrrolo[1,2-a]pyrazin-4-yl)azetidin-1-yl)quinoline 36.25

2-(3-(6-(3- methoxyphenyl)imidazo[1,2-a]pyrazin-5-yl)azetidin-1-yl)quinoline 36.26

2-(3-(6-(3- methoxyphenyl)imidazo[1,5-a]pyrazin-5-yl)azetidin-1-yl)quinoline 36.27

2-(3-(3-(3-methoxyphenyl)-6- (oxetan-3-yl)pyrazin-2-yl)azetidin-1-yl)quinoline 36.28

2-(3-(6-(azetidin-3-yl)-3-(3- methoxyphenyl)pyrazin-2-yl)azetidin-1-yl)quinoline 36.29

4-(5-(3-methoxyphenyl)-6-(1- (quinolin-2-yl)azetidin-3-yl)pyrazin-2-yl)oxazole 36.30

3-(5-(3-methoxyphenyl)-6-(1- (quinolin-2-yl)azetidin-3-yl)pyrazin-2-yl)-1,2,4-oxadiazole 36.31

1,1,1-trifluoro-2-(5-(3- methoxyphenyl)-6-(1-(quinolin-2-yl)azetidin-3-yl)pyrazin-2-yl)propan- 2-ol 36.32

N-((5-(3-methoxyphenyl)-6-(1- (quinazolin-2-yl)azetidin-3-yl)pyrazin-2-yl)methyl)acetamide 36.33

2-(3-(3-(3-methoxyphenyl)-6- (tetrahydrofuran-2-yl)pyrazin-2-yl)azetidin-1-yl)quinazoline 36.34

2-(3-(3-(3-methoxyphenyl)-6- (oxetan-2-yl)pyrazin-2-yl)azetidin-1-yl)quinazoline 36.35

6-(3-methoxyphenyl)-5-(1-(quinolin- 2-yl)azetidin-3-yl)pyrazine-2-carbonitrile 36.36

2-(3-methoxyphenyl)-3-(1-(quinolin- 2-yl)azetidin-3-yl)-6,7-dihydro-5H-cyclopenta[b]pyrazin-5-one 36.37

3-(3-methoxyphenyl)-2-(1- (quinazolin-2-yl)azetidin-3-yl)-6,7-dihydro-5H-cyclopenta[b]pyrazin-5- one 36.38

2-(3-methoxyphenyl)-3-(1- (quinazolin-2-yl)azetidin-3-yl)-5H-pyrrolo[2,3-b]pyrazin-6(7H)-one 36.39

1-(6-(3-methoxyphenyl)-5-(1- (quinazolin-2-yl)azetidin-3-yl)pyrazin-2-yl)ethanol 36.40

(6-(3-methoxyphenyl)-5-(1- (quinazolin-2-yl)azetidin-3-yl)pyrazin-2-yl)methanol 36.41

5-(3-methoxyphenyl)-6-(1-(quinolin- 2-yl)azetidin-3-yl)pyrazine-2-carboxamide 36.42

5-(3-methoxyphenyl)-6-(1-(quinolin- 2-yl)azetidin-3-yl)pyrazine-2-carbonitrile 36.43

1-(5-(3-methoxyphenyl)-6-(1- (quinolin-2-yl)azetidin-3-yl)pyrazin-2-yl)ethanone 36.44

1-(5-(3-methoxyphenyl)-6-(1- (quinolin-2-yl)azetidin-3-yl)pyrazin-2-yl)ethanol 36.45

2-(5-(3-methoxyphenyl)-6-(1- (quinolin-2-yl)azetidin-3-yl)pyrazin-2-yl)propan-2-ol 36.46

(5-(3-methoxyphenyl)-6-(1- (quinazolin-2-yl)azetidin-3-yl)pyrazin-2-yl)methanol 36.47

1-(6-(3-methoxyphenyl)-5-(1- (quinazolin-2-yl)azetidin-3-yl)pyrazin-2-yl)ethanone 36.48

(S)-1-(3-(3-(1-(6-chloroquinazolin-2- yl)azetidin-3-yl)pyrazin-2-yl)-3-(trifluoromethyl)pyrrolidin-1- yl)ethanone 36.49

(S)-1-(3-(3-(1-(6-chloroquinolin-2- yl)azetidin-3-yl)pyrazin-2-yl)-3-(trifluoromethyl)pyrrolidin-1- yl)ethanone 36.50

(S)-1-(3-(3-(1-(6-fluoroquinazolin-2- yl)azetidin-3-yl)pyrazin-2-yl)-3-(trifluoromethyl)pyrrolidin-1- yl)ethanone 36.51

(S)-1-(3-(3-(1-(6-fluoroquinolin-2- yl)azetidin-3-yl)pyrazin-2-yl)-3-(trifluoromethyl)pyrrolidin- 1-yl)ethanone 36.52

(R)-1-(3-(3-(1-(6-chloroquinazolin-2- yl)azetidin-3-yl)pyrazin-2-yl)-3-(trifluoromethyl)pyrrolidin-1- yl)ethanone 36.53

(R)-1-(3-(3-(1-(6-chloroquinolin-2- yl)azetidin-3-yl)pyrazin-2-yl)-3-(trifluoromethyl)pyrrolidin-1- yl)ethanone 36.54

(R)-1-(3-(3-(1-(6-fluoroquinazolin-2- yl)azetidin-3-yl)pyrazin-2-yl)-3-(trifluoromethyl)pyrrolidin-1- yl)ethanone 36.55

(R)-1-(3-(3-(1-(6-fluoroquinolin-2- yl)azetidin-3-yl)pyrazin-2-yl)-3-(trifluoromethyl)pyrrolidin-1- yl)ethanone 36.56

6-(3-(3-(4-cyanopiperidin-1- yl)pyrazin-2-yl)azetidin-1-yl)-N-phenylnicotinamide 36.57

1-(3-(1-(4-methylquinolin-2- yl)azetidin-3-yl)pyrazin-2-yl)piperidine-4-carbonitrile 36.58

1-(3-(1-(4-chloroquinolin-2- yl)azetidin-3-yl)pyrazin-2-yl)piperidine-4-carbonitrile 36.59

1-(3-(1-(6-methoxy-4- methylquinolin-2-yl)azetidin-3-yl)pyrazin-2-yl)piperidine-4- carbonitrile 36.60

1-(3-(1-(4-methoxyquinazolin-2- yl)azetidin-3-yl)pyrazin-2-yl)piperidine-4-carbonitrile 36.61

1-(3-(1-(3-methylquinolin-2- yl)azetidin-3-yl)pyrazin-2-yl)piperidine-4-carbonitrile 36.62

1-(3-(1-(4,7-dimethylquinolin-2- yl)azetidin-3-yl)pyrazin-2-yl)piperidine-4-carbonitrile 36.63

1-(3-(1-(8-hydroxyquinolin-2- yl)azetidin-3-yl)pyrazin-2-yl)piperidine-4-carbonitrile 36.64

1-(3-(1-(3-chloroquinolin-2- yl)azetidin-3-yl)pyrazin-2-yl)piperidine-4-carbonitrile 36.65

1-(3-(1-(6-methylquinolin-2- yl)azetidin-3-yl)pyrazin-2-yl)piperidine-4-carbonitrile 36.66

1-(3-(1-(7-methoxy-4- methylquinolin-2-yl)azetidin-3-yl)pyrazin-2-yl)piperidine-4- carbonitrile 36.67

1-(3-(1-(4,8-dimethylquinolin-2- yl)azetidin-3-yl)pyrazin-2-yl)piperidine-4-carbonitrile 36.68

1-(3-(1-(5-(trifluoromethyl)quinolin- 2-yl)azetidin-3-yl)pyrazin-2-yl)piperidine-4-carbonitrile 36.69

1-(3-(1-(6-methoxyquinolin-2- yl)azetidin-3-yl)pyrazin-2-yl)piperidine-4-carbonitrile 36.70

1-(3-(1-(7-chloroquinolin-2- yl)azetidin-3-yl)pyrazin-2-yl)piperidine-4-carbonitrile 36.71

1-(3-(1-(5-chloroquinolin-2- yl)azetidin-3-yl)pyrazin-2-yl)piperidine-4-carbonitrile 36.72

1-(3-(1-(8-chloroquinolin-2- yl)azetidin-3-yl)pyrazin-2-yl)piperidine-4-carbonitrile 36.73

1-(3-(1-(6-chloro-4-methylquinolin- 2-yl)azetidin-3-yl)pyrazin-2-yl)piperidine-4-carbonitrile 36.74

1-(3-(1-(5-methyl-1,6-naphthyridin- 2-yl)azetidin-3-yl)pyrazin-2-yl)piperidine-4-carbonitrile 36.75

1-(3-(1-(8-methyl-4- (trifluoromethyl)quinolin-2-yl)azetidin-3-yl)pyrazin-2- yl)piperidine-4-carbonitrile 36.76

1-(3-(1-(7-chloro-4-methylquinolin- 2-yl)azetidin-3-yl)pyrazin-2-yl)piperidine-4-carbonitrile 36.77

2-(3-(3-(4-cyanopiperidin-1- yl)pyrazin-2-yl)azetidin-1-yl)quinoline-4-carbonitrile 36.78

1-(3-(1-(3-methyl-6- (trifluoromethyl)quinolin-2-yl)azetidin-3-yl)pyrazin-2- yl)piperidine-4-carbonitrile 36.79

1-(3-(1-(3,7-dimethylquinolin-2- yl)azetidin-3-yl)pyrazin-2-yl)piperidine-4-carbonitrile 36.80

1-(3-(1-(4-chloro-6-methylquinolin- 2-yl)azetidin-3-yl)pyrazin-2-yl)piperidine-4-carbonitrile 36.81

1-(3-(1-(4-methyl-7,8-dihydro-6H- cyclopenta[g]quinolin-2-yl)azetidin-3-yl)pyrazin-2-yl)piperidine-4- carbonitrile 36.82

1-(3-(1-(8-methoxyquinolin-2- yl)azetidin-3-yl)pyrazin-2-yl)piperidine-4-carbonitrile 36.83

1-(3-(1-(6-fluoro-4-methylquinolin- 2-yl)azetidin-3-yl)pyrazin-2-yl)piperidine-4-carbonitrile 36.84

1-(3-(1-(4-chloro-6- methoxyquinolin-2-yl)azetidin-3-yl)pyrazin-2-yl)piperidine-4- carbonitrile 36.85

1-(3-(1-(4-(trifluoromethyl)quinolin- 2-yl)azetidin-3-yl)pyrazin-2-yl)piperidine-4-carbonitrile 36.86

1-(3-(1-(6-chloroquinolin-2- yl)azetidin-3-yl)pyrazin-2-yl)piperidine-4-carbonitrile 36.87

1-(3-(1-(6-chloro-1,5-naphthyridin-2- yl)azetidin-3-yl)pyrazin-2-yl)piperidine-4-carbonitrile 36.88

1-(3-(1-(6-bromoquinolin-2- yl)azetidin-3-yl)pyrazin-2-yl)piperidine-4-carbonitrile 36.89

1-(3-(1-(7-fluoro-4-methylquinolin- 2-yl)azetidin-3-yl)pyrazin-2-yl)piperidine-4-carbonitrile 36.90

1-(3-(1-(6,7-dimethoxyquinazolin- 2-yl)azetidin-3-yl)pyrazin-2-yl)piperidine-4-carbonitrile 36.91

1-(3-(1-(4-fluoroquinolin-2- yl)azetidin-3-yl)pyrazin-2-yl)piperidine-4-carbonitrile 36.92

1-(3-(1-(7-bromoquinolin-2- yl)azetidin-3-yl)pyrazin-2-yl)piperidine-4-carbonitrile 36.93

1-(3-(1-(6,8-dimethyl-1,5- naphthyridin-2-yl)azetidin-3-yl)pyrazin-2-yl)piperidine-4- carbonitrile 36.94

1-(3-(1-(3-methyl-8- (trifluoromethyl)quinolin-2-yl)azetidin-3-yl)pyrazin-2- yl)piperidine-4-carbonitrile 36.95

1-(3-(1-(3-methyl-6- (trifluoromethoxy)quinolin-2-yl)azetidin-3-yl)pyrazin-2- yl)piperidine-4-carbonitrile 36.96

1-(3-(1-(3-methyl-8- (trifluoromethoxy)quinolin-2-yl)azetidin-3-yl)pyrazin-2- yl)piperidine-4-carbonitrile 36.97

1-(3-(1-(6-chloro-3-methylquinolin- 2-yl)azetidin-3-yl)pyrazin-2-yl)piperidine-4-carbonitrile 36.98

1-(3-(1-(6-fluoroquinolin-2- yl)azetidin-3-yl)pyrazin-2-yl)piperidine-4-carbonitrile 36.99

1-(3-(1-(6-(trifluoromethyl)quinolin- 2-yl)azetidin-3-yl)pyrazin-2-yl)piperidine-4-carbonitrile 36.100

2-(3-(3-(4-cyanopiperidin-1- yl)pyrazin-2-yl)azetidin-1-yl)quinoline-6-carbonitrile 36.101

1-(3-(1-(6-bromoquinazolin-2- yl)azetidin-3-yl)pyrazin-2-yl)piperidine-4-carbonitrile 36.102

1-(3-(1-(7-fluoroquinolin-2- yl)azetidin-3-yl)pyrazin-2-yl)piperidine-4-carbonitrile 36.103

1-(3-(1-(4-chloro-6-fluoroquinolin- 2-yl)azetidin-3-yl)pyrazin-2-yl)piperidine-4-carbonitrile 36.104

1-(3-(1-(pyrido[4,3-d]pyrimidin-2- yl)azetidin-3-yl)pyrazin-2-yl)piperidine-4-carbonitrile 36.105

1-(3-(1-(8-methoxyquinazolin-2- yl)azetidin-3-yl)pyrazin-2-yl)piperidine-4-carbonitrile 36.106

1-(3-(1-(7-methoxyquinazolin-2- yl)azetidin-3-yl)pyrazin-2-yl)piperidine-4-carbonitrile 36.107

1-(3-(1-(4-chloro-6- (trifluoromethyl)quinazolin-2-yl)azetidin-3-yl)pyrazin-2- yl)piperidine-4-carbonitrile 36.108

1-(3-(1-(4-chloro-7- (trifluoromethyl)quinazolin-2-yl)azetidin-3-yl)pyrazin-2- yl)piperidine-4-carbonitrile 36.109

1-(3-(1-(4-chloro-6- methoxyquinazolin-2-yl)azetidin-3-yl)pyrazin-2-yl)piperidine-4- carbonitrile 36.110

1-(3-(1-(4-chloro-7- methoxyquinazolin-2-yl)azetidin-3-yl)pyrazin-2-yl)piperidine-4- carbonitrile 36.111

1-(3-(1-(4-chloro-8- methoxyquinazolin-2-yl)azetidin-3-yl)pyrazin-2-yl)piperidine-4- carbonitrile 36.112

1-(3-(1-(4-chloro-5- fluoroquinazolin-2-yl)azetidin- 3-yl)pyrazin-2-yl)piperidine-4-carbonitrile 36.113

1-(3-(1-(4-chloro-6- fluoroquinazolin-2-yl)azetidin- 3-yl)pyrazin-2-yl)piperidine-4-carbonitrile 36.114

1-(3-(1-(4-chloro-7- fluoroquinazolin-2-yl)azetidin-3-yl)pyrazin-2-yl)piperidine-4- carbonitrile 36.115

1-(3-(1-(4-chloro-8- fluoroquinazolin-2-yl)azetidin-3-yl)pyrazin-2-yl)piperidine-4- carbonitrile 36.116

1-(3-(1-(4,7-dichloroquinazolin- 2-yl)azetidin-3-yl)pyrazin-2-yl)piperidine-4-carbonitrile 36.117

1-(3-(1-(4-methylquinazolin-2- yl)azetidin-3-yl)pyrazin-2-yl)piperidine-4-carbonitrile 36.118

1-(3-(1-(6-fluoro-4- methoxyquinolin-2-yl)azetidin-3-yl)pyrazin-2-yl)piperidine- 4-carbonitrile 36.119

1-(3-(1-(6-chloro-4- methoxyquinolin-2-yl)azetidin-3-yl)pyrazin-2-yl)piperidine-4- carbonitrile 36.120

1-(3-(1-(4,6-dimethoxyquinolin-2- yl)azetidin-3-yl)pyrazin-2-yl)piperidine-4-carbonitrile 36.121

1-(3-(1-(4,6-dimethoxyquinazolin-2- yl)azetidin-3-yl)pyrazin-2-yl)piperidine-4-carbonitrile 36.122

1-(3-(1-(4-methyl-6- (trifluoromethoxy)quinolin-2-yl)azetidin-3-yl)pyrazin-2- yl)piperidine-4-carbonitrile 36.123

1-(3-(1-(5-fluoroquinolin-2- yl)azetidin-3-yl)pyrazin-2-yl)piperidine-4-carbonitrile 36.124

1-(3-(1-(8-chloro-[1,3]dioxolo[4,5- g]quinazolin-6-yl)azetidin-3-yl)pyrazin-2-yl)piperidine-4- carbonitrile 36.125

1-(3-(1-(7-chloro-6-methylquinolin- 2-yl)azetidin-3-yl)pyrazin-2-yl)piperidine-4-carbonitrile 36.126

1-(3-(1-(7-bromoquinazolin-2- yl)azetidin-3-yl)pyrazin-2-yl)piperidine-4-carbonitrile 36.127

1-(3-(1-(5-bromoquinazolin-2- yl)azetidin-3-yl)pyrazin-2-yl)piperidine-4-carbonitrile 36.128

1-(3-(1-(6-chloro-1,7- naphthyridin-2- yl)azetidin-3-yl)pyrazin-2-yl)piperidine-4-carbonitrile 36.129

1-(3-(1-(1,6-naphthyridin-2- yl)azetidin-3-yl)pyrazin-2-yl)piperidine-4-carbonitrile 36.130

1-(3-(1-(4-chloropyrido[3,2- d]pyrimidin-2-yl)azetidin-3-yl)pyrazin-2-yl)piperidine-4- carbonitrile 36.131

1-(3-(1-(1,7-naphthyridin-2- yl)azetidin-3-yl)pyrazin-2-yl)piperidine-4-carbonitrile 36.132

1-(3-(1-(6-fluoroquinazolin-2- yl)azetidin-3-yl)pyrazin-2-yl)piperidine-4-carbonitrile 36.133

1-(3-(1-(7-fluoroquinazolin-2- yl)azetidin-3-yl)pyrazin-2-yl)piperidine-4-carbonitrile 36.134

1-(3-(1-(6-methoxy-1,7- naphthyridin-2-yl)azetidin-3-yl)pyrazin-2-yl)piperidine-4- carbonitrile 36.135

1-(3-(1-(7-(trifluoromethyl)quinolin- 2-yl)azetidin-3-yl)pyrazin-2-yl)piperidine-4-carbonitrile 36.136

1-(3-(1-(pyrido[3,2-d]pyrimidin-2- yl)azetidin-3-yl)pyrazin-2-yl)piperidine-4-carbonitrile 36.137

1-(3-(1-(6-chloropyrido[3,2- d]pyrimidin-2-yl)azetidin-3-yl)pyrazin-2-yl)piperidine-4- carbonitrile 36.138

1-(3-(1-(1,5-naphthyridin-2- yl)azetidin-3-yl)pyrazin-2-yl)piperidine-4-carbonitrile 36.139

1-(3-(1-(7-methoxyquinolin-2- yl)azetidin-3-yl)pyrazin-2-yl)piperidine-4-carbonitrile 36.140

1-(3-(1-(3-bromo-5-methyl-1,6- naphthyridin-2-yl)azetidin-3-yl)pyrazin-2-yl)piperidine-4- carbonitrile 36.141

1-(3-(1-(6-bromopyrido[3,2- d]pyrimidin-2-yl)azetidin-3-yl)pyrazin-2-yl)piperidine-4- carbonitrile 36.142

1-(3-(1-(2-bromopyrido[3,2- d]pyrimidin-6-yl)azetidin-3-yl)pyrazin-2-yl)piperidine-4- carbonitrile 36.143

1-(3-(1-(7-chloroquinazolin-2- yl)azetidin-3-yl)pyrazin-2-yl)piperidine-4-carbonitrile 36.144

1-(3-(1-(6-chloroquinazolin-2- yl)azetidin-3-yl)pyrazin-2-yl)piperidine-4-carbonitrile 36.145

1-(3-(1-(6-methylquinazolin-2- yl)azetidin-3-yl)pyrazin-2-yl)piperidine-4-carbonitrile 36.146

1-(3-(1-(8-methylquinazolin-2- yl)azetidin-3-yl)pyrazin-2-yl)piperidine-4-carbonitrile 36.147

1-(3-(1-(8-fluoroquinolin-2- yl)azetidin-3-yl)pyrazin-2-yl)piperidine-4-carbonitrile 36.148

1-(3-(1-(pyrido[3,4-d]pyrimidin-2- yl)azetidin-3-yl)pyrazin-2-yl)piperidine-4-carbonitrile 36.149

1-(3-(1-(6-bromo-7- methoxyquinazolin-2-yl)azetidin-3-yl)pyrazin-2-yl)piperidine-4- carbonitrile 36.150

1-(3-(1-(7-bromopyrido[3,2- d]pyrimidin-2-yl)azetidin-3-yl)pyrazin-2-yl)piperidine-4- carbonitrile 36.151

1-(3-(1-(5-methoxyquinazolin-2- yl)azetidin-3-yl)pyrazin-2-yl)piperidine-4-carbonitrile 36.152

1-(3-(1-(6-methoxyquinazolin-2- yl)azetidin-3-yl)pyrazin-2-yl)piperidine-4-carbonitrile 36.153

1-(3-(1-(5-chloroquinazolin-2- yl)azetidin-3-yl)pyrazin-2-yl)piperidine-4-carbonitrile 36.154

1-(3-(1-(5,7-dimethyl-6- nitroquinolin-2-yl)azetidin-3-yl)pyrazin-2-yl)piperidine-4- carbonitrile 36.155

1-(3-(1-(6-(cyclopentyloxy)-7- methoxyquinazolin-2-yl)azetidin-3-yl)pyrazin-2-yl)piperidine-4- carbonitrile 36.156

1-(3-(1-(6,7-dimethoxyquinolin-2- yl)azetidin-3-yl)pyrazin-2-yl)piperidine-4-carbonitrile 36.157

1-(3-(1-(4,6-dichlorobenzo[d]thiazol- 2-yl)azetidin-3-yl)pyrazin-2-yl)piperidine-4-carbonitrile 36.158

1-(3-(1- ([1,3]dioxolo[4′,5′:4,5]benzo[1,2-d]thiazol-6-yl)azetidin-3-yl)pyrazin- 2-yl)piperidine-4-carbonitrile36.159

1-(3-(1-(4,6-difluorobenzo[d]thiazol- 2-yl)azetidin-3-yl)pyrazin-2-yl)piperidine-4-carbonitrile 36.160

(1-(3-(3-methyl-1-(quinolin-2- yl)azetidin-3-yl)pyrazin-2-yl)piperidin-4-yl)methanol 36.161

(1-(3-(3-(hydroxymethyl)-1- (quinolin-2-yl)azetidin-3-yl)pyrazin-2-yl)piperidin-4-yl)methanol 36.162

(1-(3-(3-chloro-1-(quinolin-2- yl)azetidin-3-yl)pyrazin-2-yl)piperidin-4-yl)methanol 36.163

3-(3-(4-(hydroxymethyl)piperidin-1- yl)pyrazin-2-yl)-1-(quinolin-2-yl)azetidine-3-carbonitrile 36.164

(1-(4-(1-(quinolin-2-yl)azetidin-3- yl)pyrimidin-5-yl)piperidin-4-yl)methanol 36.165

(1-(5-(1-(quinolin-2-yl)azetidin-3- yl)pyrimidin-4-yl)piperidin-4-yl)methanol 36.166

(1-(4-(1-(quinolin-2-yl)azetidin-3- yl)pyridin-3-yl)piperidin-4-yl)methanol 36.167

(1-(5-(1-(quinolin-2-yl)azetidin-3- yl)pyridazin-4-yl)piperidin-4-yl)methanol 36.168

(1-(3-(1-(quinolin-2-yl)azetidin-3- yl)pyridin-2-yl)piperidin-4-yl)methanol 36.169

(1-(3-(1-(quinolin-2-yl)azetidin-3- yl)pyridazin-4-yl)piperidin-4-yl)methanol 36.170

(1-(3-(1-(quinolin-2-yl)azetidin-3- yl)pyridin-4-yl)piperidin-4-yl)methanol 36.171

(1-(3-(1-(7-chloro-8-fluoroquinolin- 2-yl)azetidin-3-yl)pyrazin-2-yl)piperidin-4-yl)methanol 36.172

7-chloro-8-fluoro-2-(3-(3-(2- methoxypyridin-3-yl)pyrazin-2-yl)azetidin-1-yl)quinoline 36.173

7-chloro-2-(4-(3-(4-fluoro-3- methoxyphenyl)pyrazin-2-yl)-5,6-dihydropyridin-1(2H)-yl)quinoline 36.174

1-(7-chloroquinolin-2-yl)-4-(3-(4- fluoro-3-methoxyphenyl)pyrazin-2-yl)piperidin-2-one 36.175

1-(7-chloroquinolin-2-yl)-4-(3-(3,6- dihydro-2H-pyran-4-yl)pyrazin-2-yl)piperidin-2-one 36.176

7-chloro-2-(4-(3-(3,6-dihydro-2H- pyran-4-yl)pyrazin-2-yl)-5,6-dihydropyridin-1(2H)-yl)quinoline 36.177

1-(3-(1-(7-chloroquinolin-2-yl)- 1,2,3,6-tetrahydropyridin-4-yl)pyrazin-2-yl)piperidine-4- carbonitrile 36.178

1-(3-(1-(7-chloroquinolin-2-yl)-2- oxopiperidin-4-yl)pyrazin-2-yl)piperidine-4-carbonitrile 36.179

1-(3-(1-(7-chloro-6-fluoroquinazolin- 2-yl)-1,2,3,6-tetrahydropyridin-4-yl)pyrazin-2-yl)piperidin-4-ol 36.180

1-(7-chloro-6-fluoroquinazolin-2-yl)- 4-(3-(4-hydroxypiperidin-1-yl)pyrazin-2-yl)piperidin-2-one 36.181

3-(3-(1-(7-chloro-6-fluoroquinazolin- 2-yl)-1,2,3,6-tetrahydropyridin-4-yl)pyrazin-2-yl)benzamide 36.182

3-(3-(1-(7-chloro-6-fluoroquinazolin-2-yl)-2-oxopiperidin-4-yl)pyrazin-2- yl)benzamide 36.183

4-(3-(1-acetyl-1,2,3,6- tetrahydropyridin-4-yl)pyrazin-2-yl)-1-(7-chloro-6-fluoroquinazolin-2- yl)piperidin-2-one 36.184

1-(4-(3-(1-(7-chloro-6- fluoroquinazolin-2-yl)-1,2,3,6-tetrahydropyridin-4-yl)pyrazin-2-yl)- 5,6-dihydropyridin-1(2H)-yl)ethanone 36.185

2-(4-(3-(5,6-dihydro-2H-pyran-3- yl)pyrazin-2-yl)-5,6-dihydropyridin-1(2H)-yl)-7-fluoroquinoxaline 36.186

4-(3-(5,6-dihydro-2H-pyran-3- yl)pyrazin-2-yl)-1-(7-fluoroquinoxalin-2-yl)piperidin- 2-one 36.187

N-(3-(3-(1-(7-fluoroquinoxalin-2- yl)-2-oxopiperidin-4-yl)pyrazin-2-yl)phenyl)acetamide 36.188

N-(3-(3-(1-(7-fluoroquinoxalin-2- yl)-1,2,3,6-tetrahydropyridin-4-yl)pyrazin-2-yl)phenyl)acetamide 36.189

(1-(3-(1-(7-fluoroquinoxalin-2-yl)- 1,2,3,6-tetrahydropyridin-4-yl)pyrazin-2-yl)piperidin-4- yl)methanol 36.190

1-(7-fluoroquinoxalin-2-yl)-4-(3-(4- (hydroxymethyl)piperidin-1-yl)pyrazin-2-yl)piperidin-2-one

BIOLOGICAL EXAMPLES

The above PDE10 IC₅₀ data were obtained by using the following assays.

Example A MPDE10A7 Enzyme Activity and Inhibition

Enzyme Activity. An IMAP TR-FRET assay was used to analyze the enzymeactivity (Molecular Devices Corp., Sunnyvale Calif.). 5 μL of serialdiluted PDE10A (BPS Bioscience, San Diego, Calif.) or tissue homogenatewas incubated with equal volumes of diluted fluorescein labeled cAMP orcGMP for 60 min in 384-well polystyrene assay plates (Corning, Corning,N.Y.) at room temperature. After incubation, the reaction was stopped byadding 60 μL of diluted binding reagents and was incubated for 3 hoursto overnight at room temperature. The plates were read on an Envision(Perkin Elmer, Waltham, Mass.) for time resolved fluorescence resonanceenergy transfer. The data were analyzed with GraphPad Prism (La Jolla,Calif.).

Enzyme Inhibition. To check the inhibition profile, 5 μL of serialdiluted compounds were incubated with 5 μL of diluted PDE10 enzyme (BPSBioscience, San Diego, Calif.) or tissue homogenate in a 384-wellpolystyrene assay plate (Corning, Corning, N.Y.) for 30 min at roomtemperature. After incubation, 10 μL of diluted fluorescein labeled cAMPor cGMP substrate were added and incubated for 60 min at roomtemperature. The reaction was stopped by adding 60 μL of diluted bindingreagents and plates were read on an Envision (Perkin Elmer, Waltham,Mass.) for time resolved fluorescence resonance energy transfer. Thedata were analyzed with GraphPad Prism (La Jolla, Calif.).

Example B Apomorphine Induced Deficits in Prepulse Inhibition of theStartle Response in Rats, an In Vivo Test for Antipsychotic Activity

The thought disorders that are characteristic of schizophrenia mayresult from an inability to filter, or gate, sensorimotor information.The ability to gate sensorimotor information can be tested in manyanimals as well as in humans. A test that is commonly used is thereversal of apomorphine-induced deficits in the prepulse inhibition ofthe startle response. The startle response is a reflex to a suddenintense stimulus such as a burst of noise. In this example, rats can beexposed to a sudden burst of noise, at a level of 120 db for 40 msec,e.g., the reflex activity of the rats can be measured. The reflex of therats to the burst of noise may be attenuated by preceding the startlestimulus with a stimulus of lower intensity, at 3 db to 12 db abovebackground (65 db), which attenuates the startle reflex by 20% to 80%.

The prepulse inhibition of the startle reflex, described above, may beattenuated by drugs that affect receptor signaling pathways in the CNS.One commonly used drug is the dopamine receptor agonist apomorphine.Administration of apomorphine reduces the inhibition of the startlereflex produced by the prepulse. Antipsychotic drugs such as haloperidolprevents apomorphine from reducing the prepulse inhibition of thestartle reflex. This assay can be used to test the antipsychoticefficacy of PDE10 inhibitors, as they reduce the apomorphine-induceddeficit in the prepulse inhibition of startle.

Example C Conditioned Avoidance Responding (CAR) in Rats, an In VivoTest for Antipsychotic Activity

Conditioned avoidance responding (CAR) occurs, for instance, when ananimal learns that a tone and light predict the onset of a mild footshock. The subject learns that when the tone and light are on, it mustleave the chamber and enter a safe area. All known antipsychotic drugsreduce this avoidance response at doses which do not cause sedation.Examining the ability of test compounds to suppress the conditionedavoidance has been widely used for close to fifty years to screen fordrugs with useful antipsychotic properties.

In this example, an animal can be placed in a two-chambered shuttle boxand presented with a neutral conditioned stimulus (CS) consisting of alight and tone, followed by an aversive unconditioned stimulus (US)consisting of a mild foot shock through a floor grid in the shuttle boxchamber. The animal can be free to escape the US by running from onechamber to the other, where the grid is not electrified. After severalpresentations of the CS-US pair, the animal typically learns to leavethe chamber during the presentation of the CS and avoid the USaltogether. Animals treated with clinically-relevant doses ofantipsychotic drugs have a suppression of their rate of avoidances inthe presence of the CS even though their escape response to the shockitself is unaffected.

Specifically, conditioned avoidance training can be conducted using ashuttle box (Med Associates, St. Albans, Vt.). The shuttle box istypically divided into 2 equal compartments that each contain a lightsource, a speaker that emits an 85 dB tone when activated and anelectrified grid that can deliver a scrambled foot shock. Sessions canconsist of 20 trials per day (intertrial interval of 25-40 sec) duringwhich a 10 sec illumination and a concurrent 10 sec tone signals thesubsequent delivery of a 0.5 mA shock applied for a maximum of 10 sec.Active avoidance, defined as the crossing into the opposite compartmentduring the 10 sec conditioning stimuli (light and tone) prevents thedelivery of the shock. Crossing over to the other compartment after thedelivery of the shock terminates shock delivery and may be recorded asan escape response. If an animal does not leave the conditioning chamberduring the delivery of the shock it is recorded as an escape failure.Training can be continued daily until the avoidance of 16 or more shocksout of 20 trials (80% avoidance) on 2 consecutive days is achieved.After this criterion is reached the rats may be given one day ofpharmacological testing. On test day, rats can be randomly assigned toexperimental groups, weighed and injected intraperitoneally (i.p.) (1 cctuberculin syringe, 26 3/8 gauge needle) or per os (p.o.) (18 gaugefeeding needle) with either control or compound solutions. Compounds canbe injected at 1.0 ml/kg for i.p. and 10 mL/kg for p.o. administration.Compounds can be administered either acutely or chronically. Fortesting, each rat may be placed in the shuttle box, and given 20 trialswith the same parameters as described above for training trials. Thenumber of avoidances, escapes, and escape failures can be recorded.

Example D PCP-Induced Hyperactivity (PCP-LMA)

Equipment Used: 4×8 home cage photobeam activity system (PAS) frame fromSan Diego Instruments. Open PAS program and prepare an experimentalsession using the following variables:

Multiphase experiment

300 sec/interval (5 min)

12 intervals (1 h)

Individual on screen switches.

Start recording after first beam break.

End session after end of interval.

Cage Preparation:

Techniplast™ rat cage with filter top, but no wire lid. Place ˜400 mLbedding and one food pellet in cage and place 250 mL techniplast waterbottle in holder on filter top. Place the prepped cage in the PAS frame.Make sure bedding or pellet doesn't block the photobeams.

Animal Preparation:

Mark rats and record their weights. Bring rats to testing room.

Phase I: Habituation

Start the experiment session. Place the rat in the enclosure. Thecomputer should start recording when it detects the rat breaking thebeam. The computer will record for 1 h. During the habituation phase,prepare risperidone (positive control): Measure out risperidone,calculate final volume at 1 mg/mL concentration and add 1% glacialacetic acid of the final volume to dissolve risperidone. Whenrisperidone is dissolved, add saline to final volume to make aconcentration of 1 mg/mL. Fill syringes (3 mL syringes with 23 g½ needleor oral gavage needle) with Amgen compound solution (5 mL/kg) orrisperidone (1 mL syringe with 23 g½ needle) control (1 mL/kg) s.c.

Phase II: Compound Pre-Treatment

Make sure Phase I has ended. Remove rat from enclosure, start the nextphase using on-screen individual switch, administer compound p.o or i.p.and control s.c. and place rat back in the enclosure. The computershould start recording when it detects the rat breaking the beam. Thecomputer will record for 1 h.

During phase II, prepare pcp: Dissolve pcp in saline to a concentrationof 5 mg/mL.

Fill syringes (1 mL syringes with 26 g⅜ needle) with pcp solution (1mL/kg).

Phase III: PCP Administration.

Make sure phase II is ended. Remove rat from enclosure, start the nextphase using on-screen individual switch, administer pcp s.c. and placerat back in the enclosure. The computer will record for 1 h.

Clean-Up:

End-session to terminate experiment and so that computer will compiledata. Export raw data to spreadsheet file for data analysis. Euthanizerats and take necessary tissue/sample for PK.

Data Generation:

Export raw data to spreadsheet file for data analysis. Total time ofmovement is recorded as the number of photobeam breaks by the computer.Total time of movement (seconds) is combined into 5 minute bins andaveraged for each treatment group for an N of 7-10 animals. Data areanalyzed for statistical significance using a two-way ANOVA followed bya Bonferroni's post-hoc test for multiple comparisons.

The foregoing is merely illustrative of the invention and is notintended to limit the invention to the disclosed compounds. Variationsand changes which are obvious to one skilled in the art are intended tobe within the scope and nature of the invention which are defined in theappended claims. All patents, patent applications, and otherpublications recited herein are hereby incorporated by reference intheir entirety.

1. A compound of formula I:

or a pharmaceutically acceptable salt thereof, wherein: X¹ is N or CR⁶;X² is N or CR²; X³ is N or CR³; X⁴ is N or CR⁶; X⁵ is N or CR⁶; wherein1 to 2 of X¹, X², X³, X⁴ and X⁵ are N; R¹ is halo, C₁₋₈alk, C₁₋₄haloalk,—OR^(c), —N(R^(a))C(═O)R^(b), —C(═O)R^(a), —C(═O)R^(c), —C(═O)—R^(a),—NR^(a)R^(c), —N(R^(c))C(═O)R^(b), —N(R^(a))C(═O)R^(c),—C(═O)NR^(a)R^(b), —C(═O)NR^(a)R^(c), or C₀₋₄alk-L¹; wherein saidC₁₋₈alk group is substituted by 0, 1, 2 or 3 groups which are halo,C₁₋₃haloalk, —OH, —OC₁₋₄alk, —NH₂, —NHC₁₋₄alk, —OC(═O)C₁₋₄alk, or—N(C₁₋₄alk)C₁₋₄alk; Y is a C₀₋₄alk, —C(═O), SO, or SO₂; each R² and R³is independently R¹, H, halo, CN, OH, —OC₁₋₄alk, C₁₋₄alk, C₁₋₄haloalk,—C₁₋₆alkOR^(a), —C(═O)C₁₋₄alk, —C(═O)NR^(a)R^(a), —C₀₋₄alkNH—C(═O)R^(a),or R^(c); or alternatively the ring containing X¹, X², X³, X⁴ and X⁵ canbe fused to ring A, ring B, or ring C; each having the formula:

wherein each said ring A, ring B, or ring C is a fused 4- to6-membered-saturated, -partially saturated, or -unsaturated-carbocyclicor -heterocyclic ring containing 0, 1, 2, or 3 heteroatoms; and issubstituted by 0, 1, or 2 R¹⁰ groups; R^(4a) is H, OH, halo, C₁₋₄alk, orC₁₋₄haloalk; R^(4b) is halo, CN, OH, OC₁₋₄alk, C₁₋₄alk, C₁₋₄haloalk, oroxo; R⁵ is —C₁₋₆alkOR^(a), 5- to 6-membered heteroaryl, unsaturated 9-to 10-membered bicyclo-heterocyclic ring, or 11- to 15-memberedtricyclo-heterocyclic ring; R⁵ ring is substituted by 0, 1, 2, 3, or 4R⁸ groups; R⁶ is independently R¹, H, halo, CN, OH, OC₁₋₄alk, C₁₋₄alk orC₁₋₄haloalk; m is 0, 1, 2, 3, or 4; each of p and q is independently 0,1, 2, 3, 4, 5, or 6; wherein the sum of p and q is 2 to 6; the ringcontaining p and q contains 0, 1, or 2 double bonds; R^(a) isindependently H or R^(b); R^(b) is independently phenyl, benzyl, orC₁₋₆alk, wherein said phenyl, benzyl, and C₁₋₆alk are substituted by 0,1, 2 or 3 substituents which are, independently, halo, C₁₋₄alk,C₁₋₃haloalk, —OH, —OC₁₋₄alk, —NH₂, —NHC₁₋₄alk, —OC(═O)C₁₋₄alk, or—N(C₁₋₄alk)C₁₋₄alk; R^(c) is C₀₋₄alk-L²; each L¹ is independently acarbon-linked or nitrogen-linked saturated, partially-saturated orunsaturated 3-, 4-, 5-, 6-, or 7-membered monocyclic ring or asaturated, partially-saturated or unsaturated 6-, 7-, 8-, 9-, 10-, 11-,or 12-membered bicyclic ring, said ring contains 0, 1, 2, 3, or 4 Natoms and 0, 1, or 2 atoms which are O or S; L¹ is independentlysubstituted by 0, 1, 2 or 3 R⁹ groups; each L² is independently acarbon-linked or nitrogen-linked saturated, partially-saturated orunsaturated 3-, 4-, 5-, 6-, or 7-membered monocyclic ring or asaturated, partially-saturated or unsaturated 6-, 7-, 8-, 9-, 10-, 11-,or 12-membered bicyclic ring, said ring contains 0, 1, 2, 3, or 4 Natoms and 0, 1, or 2 atoms which are O or S; L² is independentlysubstituted by 0, 1, 2 or 3 R¹¹ groups; R⁸ is halo, CN, OH, OC₁₋₄alk,C₁₋₄alk, C₁₋₄haloalk, OC₁₋₄haloalk, —C(═O)R^(b), —C(═O)R^(c),—C(═O)NHR^(b), —C(═O)NHR^(c), —S(═O)₂R^(b), —S(═O)₂R^(c),—S(═O)₂NR^(a)R^(a), R^(b), R^(c), NO₂, OR^(b), or OR^(c); R⁹ is halo,C₁₋₆alk, C₁₋₄haloalk, —OR^(a), —OC₁₋₄haloalk, CN, —C(═O)R^(b),—C(═O)OR^(a), —C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a), —OC(═O)R^(b),—OC(═O)NR^(a)R^(a), —OC₁₋₆alkNR^(a)R^(a), —OC₁₋₆alkOR^(a), —SR^(a),—S(═O)R^(b), —S(═O)₂R^(b), —S(═O)₂NR^(a)R^(a), —NR^(a)R^(a),—N(R^(a))C(═O)R^(b), —N(R^(a))C(═O)OR^(b), —N(R^(a))C(═O)NR^(a)R^(a),—N(R^(a))C(═NR^(a))NR^(a)R^(a), —N(R^(a))S(═O)₂R^(b),—N(R^(a))S(═O)₂NR^(a)R^(a), —NR^(a)C₁₋₆alkNR^(a)R^(a),—NR^(a)C₁₋₆alkOR^(a), —C₁₋₆alkNR^(a)R^(a), —C₁₋₆alkOR^(a),—C₁₋₆alkN(R^(a))C(═O)R^(b), —C₁₋₆alkOC(═O)R^(b),—C₁₋₆alkC(═O)NR^(a)R^(a), —C₁₋₆alkC(═O)OR^(a), oxo, or R^(c); R¹⁰ isoxo, C₁₋₆alk, C₁₋₃haloalk, —OH, —OC₁₋₄alk, —NH₂, —NHC₁₋₄alk,—OC(═O)C₁₋₄alk, or —N(C₁₋₄alk)C₁₋₄alk; and R¹¹ is halo, C₁₋₆alk,C₁₋₄haloalk, —OR^(a), —OC₁₋₄haloalk, CN, —C(═O)R^(b), —C(═O)OR^(a),—C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a), —OC(═O)R^(b),—OC(═O)NR^(a)R^(a), —OC₁₋₆alkNR^(a)R^(a), —OC₁₋₆alkOR^(a), —SR^(a),—S(═O)R^(b), —S(═O)₂R^(b), —S(═O)₂NR^(a)R^(a), —NR^(a)R^(a),—N(R^(a))C(═O)R^(b), —N(R^(a))C(═O)OR^(b), —N(R^(a))C(═O)NR^(a)R^(a),—N(R^(a))C(═NR^(a))NR^(a)R^(a), —N(R^(a))S(═O)₂R^(b),—N(R^(a))S(═O)₂NR^(a)R^(a), —NR^(a)C₁₋₆alkNR^(a)R^(a),—NR^(a)C₁₋₆alkOR^(a), —C₁₋₆alkNR^(a)R^(a), —C₁₋₆alkOR^(a),—C₁₋₆alkN(R^(a))C(═O)R^(b), —C₁₋₆alkOC(═O)R^(b),—C₁₋₆alkC(═O)NR^(a)R^(a), —C₁₋₆alkC(═O)OR^(a), or oxo.
 2. The compoundaccording to claim 1, or a pharmaceutically acceptable salt thereof,wherein the group


3. The compound according to claim 1, or a pharmaceutically acceptablesalt thereof, wherein the group


4. The compound according to claim 3, or a pharmaceutically acceptablesalt thereof, wherein each of said Ring A, Ring B, and Ring C is a fused4- to 6-membered-saturated, -partially saturated, or-unsaturated-carbocyclic which are fused phenyl, cyclobutyl,cyclopentyl, or cyclohexyl; said Ring A, Ring B, and Ring C issubstituted by 0, 1, or 2 R¹⁰ groups which are oxo, C₁₋₆alk,C₁₋₃haloalk, —OH, —OC₁₋₄alk, —NH₂, —NHC₁₋₄alk, —OC(═O)C₁₋₄alk, or—N(C₁₋₄alk)C₁₋₄alk.
 5. The compound according to claim 3, or apharmaceutically acceptable salt thereof, wherein each of said Ring A,Ring B, and Ring C is a fused 5-membered-saturated, -partiallysaturated, or -unsaturated-heterocyclic ring which are fused furanyl,thiophenyl, pyrrolyl, pyrrolinyl, pyrrolidinyl, dioxolanyl, oxazolyl,thiazolyl, isothiazolyl, imidazolyl, imidazolinyl, imidazolidinyl,pyrazolyl, pyrazolinyl, pyrazolidinyl, isoxazolyl, or isothiazolyl; saidRing A, Ring B, and Ring C is substituted by 0, 1, or 2 R¹⁰ groups whichare oxo, C₁₋₆alk, C₁₋₃haloalk, —OH, —OC₁₋₄alk, —NH₂, —NHC₁₋₄alk,—OC(═O)C₁₋₄alk, or —N(C₁₋₄alk)C₁₋₄alk.
 6. The compound according toclaim 3, or a pharmaceutically acceptable salt thereof, wherein each ofsaid Ring A, Ring B, and Ring C is a fused 6-membered-saturated,-partially saturated, or -unsaturated-heterocyclic ring which are fusedpyranyl, pyridinyl, piperidinyl, dioxanyl, morpholinyl, dithianyl,thiomorpholinyl, pyridazinyl, pyrazinyl, or piperazinyl; said Ring A,Ring B, and Ring C is substituted by 0, 1, or 2 R¹⁰ groups which areoxo, C₁₋₆alk, C₁₋₃haloalk, —OH, —OC₁₋₄alk, —NH₂, —NHC₁₋₄alk,—OC(═O)C₁₋₄alk, or —N(C₁₋₄alk)C₁₋₄alk.
 7. The compound according toclaim 1, or a pharmaceutically acceptable salt thereof, wherein each ofp and q is independently
 1. 8. The compound according to claim 1, or apharmaceutically acceptable salt thereof, wherein each of p and q isindependently
 2. 9. The compound according to claim 8, or apharmaceutically acceptable salt thereof, wherein the ring containing pand q contains 0 or 1 double bond.
 10. The compound according to claim1, or a pharmaceutically acceptable salt thereof, wherein the sum of pand q is 3; and the ring containing p and q contains 0 or 1 double bond.11. The compound according to claim 9, or a pharmaceutically acceptablesalt thereof, wherein R^(4b) is oxo and m is
 1. 12. The compoundaccording to claim 11, or a pharmaceutically acceptable salt thereof,wherein R⁵ is unsaturated 10-membered bicyclo-heterocyclic ring; whereineach R⁵ ring is substituted by 0, 1, or 2 R⁸ groups.
 13. The compoundaccording to claim 1, or a pharmaceutically acceptable salt thereof,wherein the group

wherein each

is substituted by 0, 1, or 2 R¹⁰ groups.
 14. The compound according toclaim 1, or a pharmaceutically acceptable salt thereof, wherein m is 1or
 2. 15. The compound according to claim 1, or a pharmaceuticallyacceptable salt thereof, wherein R¹ is —NR^(a)R^(c), —OR^(c) or—C₀₋₄alk-L¹.
 16. The compound according to claim 1, or apharmaceutically acceptable salt thereof, wherein L¹ is acarbon-linked-saturated or partially-saturated 3-, 4-, 5-, 6-, or7-membered monocyclic ring, wherein each said ring contains 0, 1, or 2 Natoms and 0 or 1 O atoms, and wherein each said L¹ is substituted by 0,1 or 2 R⁹ groups which are F, Cl, Br, C₁₋₆alk, —OR^(a), CN, —C(═O)R^(b),C(═O)OR^(a), —C(═O)NR^(a)R^(a), —SR^(a), —S(═O)R^(b), —S(═O)₂R^(b),—NR^(a)R^(a), —N(R^(a))C(═O)R^(b), —N(R^(a))C(═O)OR^(b), —C₁₋₆alkOR^(a),—C₁₋₆alkN(R^(a))C(═O)R^(b), —C₁₋₆alkOC(═O)R^(b),—C₁₋₆alkC(═O)NR^(a)R^(a), —C₁₋₆alkC(═O)OR^(a), oxo, or R^(c).
 17. Thecompound according to claim 1, or a pharmaceutically acceptable saltthereof, wherein L¹ is a carbon-linked-saturated or partially-saturated5- to 6-membered monocyclic ring, wherein each said ring contains 0, 1,or 2 N atoms and 0 or 1 O atoms, and wherein each said L¹ is substitutedby 0, 1 or 2 R⁹ groups which are F, Cl, Br, C₁₋₆alk, —OR^(a), CN,—C(═O)R^(b), C(═O)OR^(a), —C(═O)NR^(a)R^(a), —SR^(a), —S(═O)R^(b),—S(═O)₂R^(b), —NR^(a)R^(a), —N(R^(a))C(═O)R^(b), —N(R^(a))C(═O)OR^(b),—C₁₋₆alkOR^(a), —C₁₋₆alkN(R^(a))C(═O)R^(b), —C₁₋₆alkOC(═O)R^(b),—C₁₋₆alkC(═O)NR^(a)R^(a), —C₁₋₆alkC(═O)OR^(a), oxo, or R^(c).
 18. Thecompound according to claim 1, or a pharmaceutically acceptable saltthereof, wherein L¹ is a carbon-linked-unsaturated 5- to 6-memberedmonocyclic ring, wherein each said ring contains 0, 1, or 2 N atoms and0 or 1 O atoms, and wherein each said L¹ is substituted by 0, 1 or 2 R⁹groups which are F, Cl, Br, C₁₋₆alk, —OR^(a), CN, —C(═O)R^(b),C(═O)OR^(a), —C(═O)NR^(a)R^(a), —SR^(a), —S(═O)R^(b), —S(═O)₂R^(b),—NR^(a)R^(a), —N(R^(a))C(═O)R^(b), —N(R^(a))C(═O)OR^(b), —C₁₋₆alkOR^(a),—C₁₋₆alkN(R^(a))C(═O)R^(b), —C₁₋₆alkOC(═O)R^(b),—C₁₋₆alkC(═O)NR^(a)R^(a), —C₁₋₆alkC(═O)OR^(a), oxo, or R^(c).
 19. Thecompound according to claim 1, or a pharmaceutically acceptable saltthereof, wherein L¹ is a carbon-linked-saturated, partially-saturated orunsaturated 6-, 7-, 8-, 9-, or 10-membered bicyclic ring, wherein eachsaid ring contains 0, 1, or 2 N atoms and 0 or 1 O atoms, and whereineach said L¹ is substituted by 0, 1 or 2 R⁹ groups which are F, Cl, Br,C₁₋₆alk, —OR^(a), CN, —C(═O)R^(b), C(═O)OR^(a), —C(═O)NR^(a)R^(a),—SR^(a), —S(═O)R^(b), —S(═O)₂R^(b), —NR^(a)R^(a), —N(R^(a))C(═O)R^(b),—N(R^(a))C(═O)OR^(b), —C₁₋₆alkOR^(a), —C₁₋₆alkN(R^(a))C(═O)R^(b),—C₁₋₆alkOC(═O)R^(b), —C₁₋₆alkC(═O)NR^(a)R^(a), —C₁₋₆alkC(═O)OR^(a), oxo,or R^(c).
 20. The compound according to claim 1, or a pharmaceuticallyacceptable salt thereof, wherein L¹ is a nitrogen-linked saturated,partially-saturated or unsaturated 4-, 5-, 6-, or 7-membered monocyclicring, wherein said ring contains 0, 1, 2, 3, or 4 N atoms and 0 or 1 Oatoms, and wherein each said L¹ is substituted by 0, 1 or 2 R⁹ groupswhich are F, Cl, Br, C₁₋₆alk, —OR^(a), CN, —C(═O)R^(b), C(═O)OR^(a),—C(═O)NR^(a)R^(a), —SR^(a), —S(═O)R^(b), —S(═O)₂R^(b), —NR^(a)R^(a),—N(R^(a))C(═O)R^(b), —N(R^(a))C(═O)OR^(b), —C₁₋₆alkOR^(a),—C₁₋₆alkN(R^(a))C(═O)R^(b), —C₁₋₆alkOC(═O)R^(b),—C₁₋₆alkC(═O)NR^(a)R^(a), —C₁₋₆alkC(═O)OR^(a), oxo, or R^(c).
 21. Thecompound according to claim 1, or a pharmaceutically acceptable saltthereof, wherein L¹ is a nitrogen-linked saturated, partially-saturatedor unsaturated 6-, 7-, 8-, 9-, 10-, 11-, or 12-membered bicyclic ring,wherein each said ring contains 0, 1, or 2 N atoms and 0 or 1 O atoms,and wherein each said L¹ is substituted by 0, 1 or 2 R⁹ groups which areF, Cl, Br, C₁₋₆alk, —OR^(a), CN, —C(═O)R^(b), C(═O)OR^(a),—C(═O)NR^(a)R^(a), —SR^(a), —S(═O)R^(b), —S(═O)₂R^(b), —NR^(a)R^(a),—N(R^(a))C(═O)R^(b), —N(R^(a))C(═O)OR^(b), —C₁₋₆alkOR^(a),—C₁₋₆alkN(R^(a))C(═O)R^(b), —C₁₋₆alkOC(═O)R^(b),—C₁₋₆alkC(═O)NR^(a)R^(a), —C₁₋₆alkC(═O)OR^(a), oxo, or R^(c).
 22. Thecompound according to claim 1, or a pharmaceutically acceptable saltthereof, wherein L¹ is -3-azabicyclo[3.1.0]hexanyl, azetidinyl, indolyl,phenyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrazolyl, piperazinonyl,piperidinyl, pyrrolidinyl, dihydropyranyl, tetrahydropyridinyl,octahydropyrrolo[3,4-c]pyrrolyl, tetrahydroisoquinolinyl, each of whichis substituted by 0, 1 or 2 R⁹ groups which are F, Cl, Br, C₁₋₆alk,—OR^(a), CN, —C(═O)R^(b), C(═O)OR^(a), —C(═O)NR^(a)R^(a), —SR^(a),—S(═O)R^(b), —S(═O)₂R^(b), —NR^(a)R^(a), —N(R^(a))C(═O)R^(b),—N(R^(a))C(═O)OR^(b), —C₁₋₆alkOR^(a), —C₁₋₆alkN(R^(a))C(═O)R^(b),—C₁₋₆alkOC(═O)R^(b), —C₁₋₆alkC(═O)NR^(a)R^(a), —C₁₋₆alkC(═O)OR^(a), oxo,or R^(c).
 23. The compound according to claim 1, or a pharmaceuticallyacceptable salt thereof, wherein R¹ is: Cl; Br; —C≡C—CH₃; —NH—CH(CH₃)₂;—NHCH₂CH₂OCH₃; —NHCH₂CH₂OH;


24. The compound according to claim 1, or a pharmaceutically acceptablesalt thereof, wherein R¹ is


25. The compound according to claim 1, or a pharmaceutically acceptablesalt thereof, wherein R¹ is:


26. The compound according to claim 1, or a pharmaceutically acceptablesalt thereof, wherein each R² and R³ is independently H, F, Cl, Br, CN,OH, OC₁₋₄alk, C₁₋₄alk or C₁₋₄haloalk.
 27. The compound according toclaim 1, or a pharmaceutically acceptable salt thereof, wherein R⁶ is H,F, or C₁₋₄alk.
 28. The compound according to claim 1, or apharmaceutically acceptable salt thereof, wherein R^(4a) is H, F, OH, ormethyl.
 29. The compound according to claim 1, or a pharmaceuticallyacceptable salt thereof, wherein R^(4b) is oxo and m is
 1. 30. Thecompound according to claim 1, or a pharmaceutically acceptable saltthereof, wherein R^(4a) is H and m is
 0. 31. The compound according toclaim 1, or a pharmaceutically acceptable salt thereof, wherein R⁵ ispyridinyl.
 32. The compound according to claim 1, or a pharmaceuticallyacceptable salt thereof, wherein R⁵ is unsaturated 9- to 10-memberedbicyclo-heterocyclic ring.
 33. The compound according to claim 1, or apharmaceutically acceptable salt thereof, wherein R⁵ is 11- to15-membered tricyclo-heterocyclic ring.
 34. The compound according toclaim 1, or a pharmaceutically acceptable salt thereof, wherein thegroup —Y—R⁵ is:

wherein each R⁵ is substituted by 1 or 2 R⁸ groups.
 35. The compoundaccording to claim 1, or a pharmaceutically acceptable salt thereof,wherein the group —Y—R⁵ is:

wherein each R⁵ is substituted by 1 or 2 R⁸ groups.
 36. The compoundaccording to claim 1, or a pharmaceutically acceptable salt thereof,wherein the group —Y—R⁵ is:


37. The compound according to claim 1, or a pharmaceutically acceptablesalt thereof, wherein Y is a bond or —C(═O).
 38. The compound accordingto claim 1, or a pharmaceutically acceptable salt thereof, wherein Y isa bond.
 39. The compound according to claim 1, or a pharmaceuticallyacceptable salt thereof, wherein R⁸ is independently F, Br, C₁, CF₃,methyl, methoxy, or CN.
 40. The compound according to claim 1, or apharmaceutically acceptable salt thereof, wherein R^(a) is H or C₁₋₆alksubstituted by 0 or 1 —OH, —OC₁₋₄alk, —OC(═O)C₁₋₄alk, or—N(C₁₋₄alk)C₁₋₄alk.
 41. The compound according to claim 1, or apharmaceutically acceptable salt thereof, wherein R^(c) is aC₀₋₄alk-carbon-linked saturated, partially-saturated or unsaturated 3-,4-5-, or 6-membered monocyclic ring containing 0, 1, or 2 N atoms and 0or 1 atom which are O or S, each R^(c) is substituted by 0 or 1 R¹¹groups which are independently F, C₁₋₆alk, C₁₋₄haloalk, or —OR^(a). 42.The compound according to claim 1, or a pharmaceutically acceptable saltthereof, wherein R^(c) is pyridyl, phenyl, or 1,2,4-oxadiazolyl.
 43. Acompound of formula II:

or a pharmaceutically acceptable salt thereof, wherein: Ring D is -L¹;X¹ is N or CR⁶; X² is N or CR²; X³ is N or CR³; X⁴ is N or CR⁶; wherein1 to 2 of X¹, X², X³, and X⁴ are N; Y is a C₀₋₄alk, —C(═O), SO, or SO₂;each R² and R³ is independently H, halo, CN, OH, —OC₁₋₄alk, C₁₋₄alk,C₁₋₄haloalk, —C(═O)C₁₋₄alk, —C(═O)NR^(a)R^(a), —C₀₋₄alkNH—C(═O)R^(a), orR^(c); or alternatively the ring containing X¹, X², X³, X⁴ and X⁵ can befused to ring A, ring B, or ring C; having the formula:

wherein each said ring A, ring B, or ring C is a fused 4- to6-membered-saturated, -partially saturated, or -unsaturated-carbocyclicor -heterocyclic ring containing 0, 1, 2, or 3 heteroatoms; and issubstituted by 0, 1, or 2 R¹⁰ groups; R^(4a) is H, OH, halo, C₁₋₄alk, orC₁₋₄haloalk; R^(4b) is halo, CN, OH, OC₁₋₄alk, C₁₋₄alk, C₁₋₄haloalk, oroxo; R⁵ is pyridinyl or unsaturated 9- to 10-memberedbicyclo-heterocyclic ring; wherein each R⁵ is substituted by 0, 1, 2 or3 R⁸ groups; R⁶ is independently H, halo, CN, OH, OC₁₋₄alk, C₁₋₄alk orC₁₋₄haloalk; m is 0, 1, 2, 3, or 4; each of p and q is independently 0,1, 2, 3, 4, 5, or 6; wherein the sum of p and q is 2 to 6; the ringcontaining p and q contains 0, 1, or 2 double bonds; R^(a) isindependently H or R^(b); R^(b) is independently phenyl, benzyl, orC₁₋₆alk, wherein said phenyl, benzyl, or C₁₋₆alk substituted by 0, 1, 2or 3 substituents which are, independently, halo, C₁₋₄alk, C₁₋₃haloalk,—OH, —OC₁₋₄alk, —NH₂, —NHC₁₋₄alk, —OC(═O)C₁₋₄alk, or —N(C₁₋₄alk)C₁₋₄alk;R^(c) is C₀₋₄alk-L²; each L¹ is independently a carbon-linked ornitrogen-linked saturated, partially-saturated or unsaturated 3-, 4-,5-, 6-, or 7-membered monocyclic ring or a saturated,partially-saturated or unsaturated 6-, 7-, 8-, 9-, 10-, 11-, or12-membered bicyclic ring, wherein each said ring contains 0, 1, 2, 3,or 4 N atoms and 0, 1, or 2 atoms which are O or S; wherein each L¹ isindependently substituted by 0, 1, 2 or 3 R⁹ groups; each L² isindependently a carbon-linked or nitrogen-linked saturated,partially-saturated or unsaturated 3-, 4-, 5-, 6-, or 7-memberedmonocyclic ring or a saturated, partially-saturated or unsaturated 6-,7-, 8-, 9-, 10-, 11-, or 12-membered bicyclic ring, wherein each saidring contains 0, 1, 2, 3, or 4 N atoms and 0, 1, or 2 atoms which are Oor S; wherein each L² is independently substituted by 0, 1, 2 or 3 R¹¹groups; R⁸ is halo, CN, OH, OC₁₋₄alk, C₁₋₄alk, C₁₋₄haloalk,OC₁₋₄haloalk, —C(═O)R^(b), —C(═O)R^(c), —C(═O)NHR^(b), —C(═O)NHR^(c),—S(═O)₂R^(b), —S(═O)₂R^(c), —S(═O)₂NR^(a)R^(a), R^(b), R^(c), NO₂,OR^(b), or OR^(c); R⁹ is F, Cl, Br, C₁₋₆alk, C₁₋₄haloalk, —OR^(a),—OC₁₋₄haloalk, CN, —C(═O)R^(b), —C(═O)OR^(a), —C(═O)NR^(a)R^(a),—C(═NR^(a))NR^(a)R^(a), —OC(═O)R^(b), —OC(═O)NR^(a)R^(a),—OC₁₋₆alkNR^(a)R^(a), —OC₁₋₆alkOR^(a), —SR^(a), —S(═O)R^(b),—S(═O)₂R^(b), —S(═O)₂NR^(a)R^(a), —NR^(a)R^(a), —N(R^(a))C(═O)R^(b),—N(R^(a))C(═O)OR^(b), —N(R^(a))C(═O)NR^(a)R^(a),—N(R^(a))C(═NR^(a))NR^(a)R^(a), —N(R^(a))S(═O)₂R^(b),—N(R^(a))S(═O)₂NR^(a)R^(a), —NR^(a)C₁₋₆alkNR^(a)R^(a),—NR^(a)C₁₋₆alkOR^(a), —C₁₋₆alkNR^(a)R^(a), —C₁₋₆alkOR^(a),—C₁₋₆alkN(R^(a))C(═O)R^(b), —C₁₋₆alkOC(═O)R^(b),—C₁₋₆alkC(═O)NR^(a)R^(a), —C₁₋₆alkC(═O)OR^(a), oxo, or R^(c); R¹⁰ isoxo, C₁₋₆alk, C₁₋₃haloalk, —OH, —OC₁₋₄alk, —NH₂, —NHC₁₋₄alk,—OC(═O)C₁₋₄alk, or —N(C₁₋₄alk)C₁₋₄alk; and R¹¹ is F, Cl, Br, C₁₋₆alk,C₁₋₄haloalk, —OR^(a), —OC₁₋₄haloalk, CN, —C(═O)R^(b), —C(═O)OR^(a),—C(═O)NR^(a)R^(a), —C(═NR^(a))NR^(a)R^(a), —OC(═O)R^(b),—OC(═O)NR^(a)R^(a), —OC₁₋₆alkNR^(a)R^(a), —OC₁₋₆alkOR^(a), —SR^(a),—S(═O)R^(b), —S(═O)₂R^(b), —S(═O)₂NR^(a)R^(a), —NR^(a)R^(a),—N(R^(a))C(═O)R^(b), —N(R^(a))C(═O)OR^(b), —N(R^(a))C(═O)NR^(a)R^(a),—N(R^(a))C(═NR^(a))NR^(a)R^(a), —N(R^(a))S(═O)₂R^(b),—N(R^(a))S(═O)₂NR^(a)R^(a), —NR^(a)C₁₋₆alkNR^(a)R^(a),—NR^(a)C₁₋₆alkOR^(a), —C₁₋₆alkNR^(a)R^(a), —C₁₋₆alkOR^(a),—C₁₋₆alkN(R^(a))C(═O)R^(b), —C₁₋₆alkOC(═O)R^(b),—C₁₋₆alkC(═O)NR^(a)R^(a), —C₁₋₆alkC(═O)OR^(a), or oxo.
 44. The compoundaccording to claim 43, wherein the group

is azetidinyl, pyrrolidinyl, piperidinyl, or azepanyl.
 45. The compoundaccording to claim 43, having the formula:


46. The compound according to claim 43, having the formula:


47. The compound according to claim 43, having the formula:


48. The compound according to claim 47, wherein R^(4b) is oxo; m is 1;and R⁵ is unsaturated 10-membered bicyclo-heterocyclic ring; whereineach R⁵ ring is substituted by 0, 1, or 2 R⁸ groups.
 49. The compoundaccording to claim 47, having the formula:

wherein m is 0; and R⁵ is unsaturated 10-membered bicyclo-heterocyclicring; wherein each R⁵ ring is substituted by 0, 1, or 2 R⁸ groups. 50.The compound according to claim 45, wherein the group —Y—R⁵ is:

Y is a bond; wherein each R⁵ is substituted by 1 or 2 R⁸ groups; and R⁸is independently F, Cl, Br, methyl, ethyl, isopropyl, methoxy, CN, CF₃,OH, or OCF₃.
 51. The compound according to claim 46, wherein the group—Y—R⁵ is:

Y is a bond; wherein each R⁵ is substituted by 1 or 2 R⁸ groups; and R⁸is independently F, Cl, Br, methyl, ethyl, isopropyl, methoxy, CN, CF₃,OH, or OCF₃.
 52. The compound according to claim 47, wherein the group—Y—R⁵ is:

Y is a bond; wherein each R⁵ is substituted by 1 or 2 R⁸ groups; and R⁸is independently F, Cl, Br, methyl, ethyl, isopropyl, methoxy, CN, CF₃,OH, or OCF₃.
 53. The compound according to claim 48, wherein the group—Y—R⁵ is:

Y is a bond; wherein each R⁵ is substituted by 1 or 2 R⁸ groups; and R⁸is independently F, Cl, Br, methyl, ethyl, isopropyl, methoxy, CN, CF₃,OH, or OCF₃.
 54. A method of treating conditions that may be treatedwith PDE10 inhibitors comprising the step of administering to a patientin need thereof a therapeutically effective amount of a compoundaccording to claim 1, or a pharmaceutically acceptable salt thereof. 55.The method according to claim 54 wherein said condition is psychoses,Parkinson's disease, dementias, obsessive compulsive disorder, tardivedyskinesia, choreas, depression, mood disorders, impulsivity, drugaddiction, attention deficit/hyperactivity disorder (ADHD), depressionwith parkinsonian states, personality changes with caudate or putamendisease, dementia and mania with caudate and pallidal diseases, orcompulsions with pallidal disease.
 56. A method of treating conditionsthat may be treated with PDE10 inhibitors comprising the step ofadministering to a patient in need thereof a therapeutically effectiveamount of a compound according to claim 43, or a pharmaceuticallyacceptable salt thereof.
 57. The method according to claim 56 whereinsaid condition is schizophrenia, Huntington disease, obesity, bipolardisorder, or obsessive-compulsive disorder.
 58. A pharmaceuticalcomposition comprising a compound according to claim 1, or apharmaceutically acceptable salt thereof, and a pharmaceuticallyacceptable excipient.
 59. The compound according to claim 1, or apharmaceutically acceptable salt thereof, which is:(1H-Benzoimidazol-2-yl)-[3-(3-phenyl-pyridin-2-yl)-azetidin-1-yl]-methanone;(1H-Benzoimidazol-2-yl)-[3-(5-fluoro-3-phenyl-pyridin-2-yl)-azetidin-1-yl]-methanone;(1H-benzoimidazol-2-yl)-[4-(3-phenyl-pyrazin-2-yl)-piperidin-1-yl]-methanone;Benzothiazol-2-yl-[3-(3-phenyl-pyrazin-2-yl)-azetidin-1-yl]-methanone;(1H-Benzoimidazol-2-yl)-[3-(3-piperidin-1-yl-quinoxalin-2-yl)-azetidin-1-yl]-methanone;(1H-Benzoimidazol-2-yl)-{3-[3-(4-hydroxy-piperidin-1-yl)-quinoxalin-2-yl]-azetidin-1-yl}-methanone;(1H-Benzoimidazol-2-yl)-[3-(2,3-dihydro-indol-1-yl)-3′,4′,5′,6′-tetrahydro-2′H-[2,4′]bipyridinyl-1′-yl]-methanone;(1H-Benzoimidazol-2-yl)-[3-(3-phenyl-quinolin-2-yl)-azetidin-1-yl]-methanone;(1H-Benzoimidazol-2-yl)-(3-phenyl-3′,4′,5′,6′-tetrahydro-2′H-[2,4′]bipyridinyl-1′-yl)-methanone;(1H-Benzoimidazol-2-yl)-{4-[3-(4-hydroxymethyl-piperidin-1-yl)-pyrazin-2-yl]-piperidin-1-yl}-methanone;(3-(3-phenylpyrazin-2-yl)azetidin-1-yl)(pyridin-2-yl)methanone;(6-methylpyridin-2-yl)(3-(3-phenylpyrazin-2-yl)azetidin-1-yl)methanone;(3-methylpyridin-2-yl)(3-(3-phenylpyrazin-2-yl)azetidin-1-yl)methanone;(5-methylpyridin-2-yl)(3-(3-phenylpyrazin-2-yl)azetidin-1-yl)methanone;(4-methylpyridin-2-yl)(3-(3-phenylpyrazin-2-yl)azetidin-1-yl)methanone;(1H-Benzoimidazol-2-yl)-[3-(3-phenyl-quinoxalin-2-yl)-azetidin-1-yl]-methanone;(1H-Benzoimidazol-2-yl)-[3-(3-morpholin-4-yl-pyrazin-2-yl)-azetidin-1-yl]-methanone;(1-Methyl-1H-benzoimidazol-2-yl)-[3-(3-phenyl-pyrazin-2-yl)-azetidin-1-yl]-methanone;[3-(3-Phenyl-pyrazin-2-yl)-azetidin-1-yl]-[1-(2,2,2-trifluoro-ethyl)-1H-benzoimidazol-2-yl]-methanone;(1H-Benzoimidazol-2-yl)-[3-(3-phenyl-pyrazin-2-yl)-azetidin-1-yl]-methanone;(1H-Benzoimidazol-2-yl)-{3-[3-(3,4-dimethoxy-phenyl)-pyrazin-2-yl]-azetidin-1-yl}-methanone;(1H-Benzoimidazol-2-yl)-{3-[3-(3-isopropyl-phenyl)-pyrazin-2-yl]-azetidin-1-yl}-methanone;(1H-Benzoimidazol-2-yl)-{3-[3-(3-trifluoromethoxy-phenyl)-pyrazin-2-yl]-azetidin-1-yl}-methanone;1H-Benzoimidazol-2-yl)-{3-[3-(3,5-dimethoxy-phenyl)-pyrazin-2-yl]-azetidin-1-yl}-methanone;(1H-Benzoimidazol-2-yl)-{3-[3-(3-ethoxy-phenyl)-pyrazin-2-yl]-azetidin-1-yl}-methanone;(1H-Benzoimidazol-2-yl)-{3-[3-(3-isopropoxy-phenyl)-pyrazin-2-yl]-azetidin-1-yl}-methanone;(1H-Benzoimidazol-2-yl)-{3-[3-(3-fluoro-5-methoxy-phenyl)-pyrazin-2-yl]-azetidin-1-yl}-methanone;(1H-Benzoimidazol-2-yl)-{3-[3-(2-methoxy-pyridin-4-yl)-pyrazin-2-yl]-azetidin-1-yl}-methanone;(1H-Benzoimidazol-2-yl)-{3-[3-(5-methoxy-pyridin-3-yl)-pyrazin-2-yl]-azetidin-1-yl}-methanone;(1H-benzo[d]imidazol-2-yl)(3-(3-(4-fluoro-3-methylphenyl)pyrazin-2-yl)azetidin-1-yl)methanone;(1H-Benzoimidazol-2-yl)-{3-[3-(4-methoxy-3-methyl-phenyl)-pyrazin-2-yl]-azetidin-1-yl}-methanone;(1H-Benzoimidazol-2-yl)-{3-[3-(3-fluoro-5-methyl-phenyl)-pyrazin-2-yl]-azetidin-1-yl}-methanone;(1H-Benzoimidazol-2-yl)-{3-[3-(5-methyl-pyridin-3-yl)-pyrazin-2-yl]-azetidin-1-yl}-methanone;(1H-Benzoimidazol-2-yl)-{3-[3-(4-methyl-thiophen-2-yl)-pyrazin-2-yl]-azetidin-1-yl}-methanone;(1H-Benzoimidazol-2-yl)-{3-[3-(1-methyl-1H-pyrazol-4-yl)-pyrazin-2-yl]-azetidin-1-yl}-methanone;(1H-Benzoimidazol-2-yl)-{3-[3-(3-hydroxymethyl-phenyl)-pyrazin-2-yl]-azetidin-1-yl}-methanone;(1H-Benzoimidazol-2-yl)-{3-[3-(4-hydroxymethyl-phenyl)-pyrazin-2-yl]-azetidin-1-yl}-methanone;1-(4-{3-[1-(1H-Benzoimidazole-2-carbonyl)-azetidin-3-yl]-pyrazin-2-yl}-phenyl)-ethanone;1-(3-{3-[1-(1H-Benzoimidazole-2-carbonyl)-azetidin-3-yl]-pyrazin-2-yl}-phenyl)-ethanone;(1H-Benzoimidazol-2-yl)-{3-[3-(3-methoxymethyl-phenyl)-pyrazin-2-yl]-azetidin-1-yl}-methanone;4-{3-[1-(1H-Benzoimidazole-2-carbonyl)-azetidin-3-yl]-pyrazin-2-yl}-N,N-dimethyl-benzamide;3-{3-[1-(1H-Benzoimidazole-2-carbonyl)-azetidin-3-yl]-pyrazin-2-yl}-N,N-dimethyl-benzamide;(1H-benzo[d]imidazol-2-yl)(3-(3-(pyridin-4-yl)pyrazin-2-yl)azetidin-1-yl)methanone;(7-chloro-1H-benzo[d]imidazol-2-yl)(3-(3-(pyridin-3-yl)pyrazin-2-yl)azetidin-1-yl)methanone;(1H-benzo[d]imidazol-2-yl)(3-(3-(2-methylpyridin-4-yl)pyrazin-2-yl)azetidin-1-yl)methanone;(1H-benzo[d]imidazol-2-yl)(3-(3-(m-tolyl)pyrazin-2-yl)azetidin-1-yl)methanone;3-(3-(1-(1H-benzo[d]imidazole-2-carbonyl)azetidin-3-yl)pyrazin-2-yl)benzonitrile(1-Methyl-1H-benzoimidazol-2-yl)-[3-(3-piperidin-1-yl-pyrazin-2-yl)-azetidin-1-yl]-methanone;{3-[3-(4-Hydroxy-piperidin-1-yl)-pyrazin-2-yl]-azetidin-1-yl}-(1-methyl-1H-benzoimidazol-2-yl)-methanone;[3-(3-Piperidin-1-yl-pyrazin-2-yl)-azetidin-1-yl]-[1-(2,2,2-trifluoro-ethyl)-1H-benzoimidazol-2-yl]-methanone;{3-[3-(4-Hydroxy-piperidin-1-yl)-pyrazin-2-yl]-azetidin-1-yl}-[1-(2,2,2-trifluoro-ethyl)-1H-benzoimidazol-2-yl]-methanone;(1H-Benzoimidazol-2-yl)-[3-(3-pyrrolidin-1-yl-pyrazin-2-yl)-azetidin-1-yl]-methanone;(1H-Benzoimidazol-2-yl)-{3-[3-(4-trifluoromethyl-piperidin-1-yl)-pyrazin-2-yl]-azetidin-1-yl}-methanone;(R &S)-(1H-Benzoimidazol-2-yl)-{3-[3-(2-methyl-piperidin-1-yl)-pyrazin-2-yl]-azetidin-1-yl}-methanone;(1H-Benzoimidazol-2-yl)-{3-[3-(3-methyl-piperidin-1-yl)-pyrazin-2-yl]-azetidin-1-yl}-methanone;(1H-Benzoimidazol-2-yl)-{3-[3-(4-methyl-piperidin-1-yl)-pyrazin-2-yl]-azetidin-1-yl}-methanone;(1H-Benzoimidazol-2-yl)-{3-[3-(4,4-dimethyl-piperidin-1-yl)-pyrazin-2-yl]-azetidin-1-yl}-methanone;(1H-Benzoimidazol-2-yl)-{3-[3-(4-hydroxymethyl-piperidin-1-yl)-pyrazin-2-yl]-azetidin-1-yl}-methanone;(1H-Benzoimidazol-2-yl)-(3-{3-[4-(1-hydroxy-1-methyl-ethyl)-piperidin-1-yl]-pyrazin-2-yl}-azetidin-1-yl)-methanone;(1H-Benzoimidazol-2-yl)-(3-{3-[4-(1-hydroxy-1-methyl-ethyl)-piperidin-1-yl]-pyrazin-2-yl}-azetidin-1-yl)-methanone;1-{3-[1-(1H-Benzoimidazole-2-carbonyl)-azetidin-3-yl]-pyrazin-2-yl}-piperidine-4-carbonitrile;(1H-Benzoimidazol-2-yl)-{3-[3-(4-methoxymethyl-piperidin-1-yl)-pyrazin-2-yl]-azetidin-1-yl}-methanone;(R &S)-(1H-Benzoimidazol-2-yl)-{3-[3-(3-methyl-pyrrolidin-1-yl)-pyrazin-2-yl]-azetidin-1-yl}-methanone;(R &S)-(1H-Benzoimidazol-2-yl)-{3-[3-(2-methyl-pyrrolidin-1-yl)-pyrazin-2-yl]-azetidin-1-yl}-methanone;(1H-Benzoimidazol-2-yl)-{3-[3-(3,4-dihydro-1H-isoquinolin-2-yl)-pyrazin-2-yl]-azetidin-1-yl}-methanone;(1H-Benzoimidazol-2-yl)-{3-[3-(1,3-dihydro-isoindol-2-yl)-pyrazin-2-yl]-azetidin-1-yl}-methanone;(R &S)-(1H-Benzoimidazol-2-yl)-{3-[3-(3-phenyl-pyrrolidin-1-yl)-pyrazin-2-yl]-azetidin-1-yl}-methanone;(R &S)-(1H-Benzoimidazol-2-yl)-{3-[3-(2-phenyl-pyrrolidin-1-yl)-pyrazin-2-yl]-azetidin-1-yl}-methanone;(1H-Benzoimidazol-2-yl)-[3-(3-cyclopentylamino-pyrazin-2-yl)-azetidin-1-yl]-methanone;(1H-Benzoimidazol-2-yl)-[3-(3-cyclohexylamino-pyrazin-2-yl)-azetidin-1-yl]-methanone;(1H-Benzoimidazol-2-yl)-[3-(3-benzylamino-pyrazin-2-yl)-azetidin-1-yl]-methanone;(1H-Benzoimidazol-2-yl)-{3-[3-(2-hydroxy-ethylamino)-pyrazin-2-yl]-azetidin-1-yl}-methanone;(1H-benzo[d]imidazol-2-yl)(3-(3-((2-methoxyethyl)amino)pyrazin-2-yl)azetidin-1-yl)methanone;1-{3-[1-(1H-Benzoimidazole-2-carbonyl)-azetidin-3-yl]-pyrazin-2-yl}-piperidine-4-carboxylicacid amide; (R &S)-(1H-Benzoimidazol-2-yl)-{3-[3-(3-hydroxymethyl-piperidin-1-yl)-pyrazin-2-yl]-azetidin-1-yl}-methanone;(1H-Benzoimidazol-2-yl)-{3-[3-(3-hydroxy-piperidin-1-yl)-pyrazin-2-yl]-azetidin-1-yl}-methanone;[3-(3-Azepan-1-yl-pyrazin-2-yl)-azetidin-1-yl]-(1H-benzoimidazol-2-yl)-methanone;[3-(3-Azetidin-1-yl-pyrazin-2-yl)-azetidin-1-yl]-(1H-benzoimidazol-2-yl)-methanone;(R)-(1H-Benzoimidazol-2-yl)-{3-[3-(2-hydroxymethyl-pyrrolidin-1-yl)-pyrazin-2-yl]-azetidin-1-yl}-methanone;(1H-Benzoimidazol-2-yl)-[3-(3-isopropylamino-pyrazin-2-yl)-azetidin-1-yl]-methanone;(S)-(1H-Benzoimidazol-2-yl)-{3-[3-(2-hydroxymethyl-pyrrolidin-1-yl)-pyrazin-2-yl]-azetidin-1-yl}-methanone;(1H-Benzoimidazol-2-yl)-(3-{3-[4-(2-hydroxy-ethyl)-piperidin-1-yl]-pyrazin-2-yl}-azetidin-1-yl)-methanone;(1H-Benzoimidazol-2-yl)-[3-(3-[1,4]oxazepan-4-yl-pyrazin-2-yl)-azetidin-1-yl]-methanone;(1H-Benzoimidazol-2-yl)-{3-[3-(4-methyl-[1,4]diazepan-1-yl)-pyrazin-2-yl]-azetidin-1-yl}-methanone;1-(4-{3-[1-(1H-Benzoimidazole-2-carbonyl)-azetidin-3-yl]-pyrazin-2-yl}-[1,4]diazepan-1-yl)-ethanone;(1H-Benzoimidazol-2-yl)-{3-[3-(4-hydroxy-azepan-1-yl)-pyrazin-2-yl]-azetidin-1-yl}-methanone;(R &S)-(1H-Benzoimidazol-2-yl)-{3-[3-(3-hydroxymethyl-pyrrolidin-1-yl)-pyrazin-2-yl]-azetidin-1-yl}-methanone;(R)-(1H-Benzoimidazol-2-yl)-{3-[3-(3-hydroxy-piperidin-1-yl)-pyrazin-2-yl]-azetidin-1-yl}-methanone;(S)-(1H-Benzoimidazol-2-yl)-{3-[3-(3-hydroxy-piperidin-1-yl)-pyrazin-2-yl]-azetidin-1-yl}-methanone;(R &S)-1-{3-[1-(1H-Benzoimidazole-2-carbonyl)-azetidin-3-yl]-pyrazin-2-yl}-piperidine-3-carbonitrile;1-{3-[1-(1H-Benzoimidazole-2-carbonyl)-azetidin-3-yl]-pyrazin-2-yl}-piperidine-4-carboxylicacid methylamide;1-{3-[1-(1H-Benzoimidazole-2-carbonyl)-azetidin-3-yl]-pyrazin-2-yl}-piperidine-4-carboxylicacid dimethylamide;1-(1-(3-(1-(1H-benzo[d]imidazole-2-carbonyl)azetidin-3-yl)pyrazin-2-yl)piperidin-4-yl)ethanone;1-(4-(3-(1-(1H-benzo[d]imidazole-2-carbonyl)azetidin-3-yl)pyrazin-2-yl)piperazin-1-yl)ethanone;(R)-(1H-benzo[d]imidazol-2-yl)(3-(3-(3-hydroxypyrrolidin-1-yl)pyrazin-2-yl)azetidin-1-yl)methanone;(S)-(1H-benzo[d]imidazol-2-yl)(3-(3-(3-hydroxypyrrolidin-1-yl)pyrazin-2-yl)azetidin-1-yl)methanone;(1H-benzo[d]imidazol-2-yl)(3-(3-(piperidin-1-yl)pyrazin-2-yl)azetidin-1-yl)methanone;(1H-benzo[d]imidazol-2-yl)(3-(3-(4-hydroxypiperidin-1-yl)pyrazin-2-yl)azetidin-1-yl)methanone;(1H-Benzoimidazol-2-yl)-{3-[3-(2-oxa-7-aza-spiro[3.5]non-7-yl)-pyrazin-2-yl]-azetidin-1-yl}-methanone;(1H-Benzoimidazol-2-yl)-{3-[3-(2-oxa-6-aza-spiro[3.3]hept-6-yl)-pyrazin-2-yl]-azetidin-1-yl}-methanone;1-(6-{3-[1-(1H-Benzoimidazole-2-carbonyl)-azetidin-3-yl]-pyrazin-2-yl}-2,6-diaza-spiro[3.3]hept-2-yl)-ethanone;2-(3-(3-(2-methoxypyridin-3-yl)pyrazin-2-yl)azetidin-1-yl)quinoline;2-(3-(3-(6-methylpyridin-3-yl)pyrazin-2-yl)azetidin-1-yl)quinoline;2-(3-(3-(2-methylpyridin-3-yl)pyrazin-2-yl)azetidin-1-yl)quinoline;2-(3-(3-(6-fluoropyridin-3-yl)pyrazin-2-yl)azetidin-1-yl)quinoline;2-(3-(3-(6-(trifluoromethyl)pyridin-3-yl)pyrazin-2-yl)azetidin-1-yl)quinoline;2-(3-(3-(2,6-dimethoxypyridin-3-yl)pyrazin-2-yl)azetidin-1-yl)quinoline;2-(3-(3-(5-fluoropyridin-3-yl)pyrazin-2-yl)azetidin-1-yl)quinoline;2-(3-(3-(6-methoxypyridin-3-yl)pyrazin-2-yl)azetidin-1-yl)quinoline2,2,2-trifluoroacetate;2-(3-(3-(6-fluoro-5-methylpyridin-3-yl)pyrazin-2-yl)azetidin-1-yl)quinoline2,2,2-trifluoroacetate;2-(3-(3-(pyridin-3-yl)pyrazin-2-yl)azetidin-1-yl)quinoline2,2,2-trifluoroacetate;2-(3-(3-(4-(methylsulfonyl)phenyl)pyrazin-2-yl)azetidin-1-yl)quinoline2,2,2-trifluoroacetate;5-(3-(1-(quinolin-2-yl)azetidin-3-yl)pyrazin-2-yl)pyridin-2-amine;5-(3-(1-(quinolin-2-yl)azetidin-3-yl)pyrazin-2-yl)pyridin-3-amine;2-(3-(3-(6-methoxypyridin-2-yl)pyrazin-2-yl)azetidin-1-yl)quinoline;2-(3-(3-(2-(trifluoromethyl)pyridin-3-yl)pyrazin-2-yl)azetidin-1-yl)quinoline2,2,2-trifluoroacetate;N,N-dimethyl-5-(3-(1-(quinolin-2-yl)azetidin-3-yl)pyrazin-2-yl)pyrimidin-2-amine2,2,2-trifluoroacetate;2-(3-(3-(4-methylpyridin-3-yl)pyrazin-2-yl)azetidin-1-yl)quinoline2,2,2-trifluoroacetate;2-(3-(3-(5-(methylsulfonyl)pyridin-3-yl)pyrazin-2-yl)azetidin-1-yl)quinoline2,2,2-trifluoroacetate;2-(3-(3-(5-methylpyridin-3-yl)pyrazin-2-yl)azetidin-1-yl)quinoline2,2,2-trifluoroacetate;2-(3-(3-(5-methoxypyridin-3-yl)pyrazin-2-yl)azetidin-1-yl)quinoline2,2,2-trifluoroacetate;2-(3-(3-(4-chloro-3-methylphenyl)pyrazin-2-yl)azetidin-1-yl)quinoline;2-(3-(3-(3-fluoro-4-methylphenyl)pyrazin-2-yl)azetidin-1-yl)quinoline;2-chloro-4-(3-(1-(quinolin-2-yl)azetidin-3-yl)pyrazin-2-yl)phenol;2-(3-(3-(3-methoxy-5-(trifluoromethyl)phenyl)pyrazin-2-yl)azetidin-1-yl)quinoline;2-(3-(3-(4-ethoxy-3-fluorophenyl)pyrazin-2-yl)azetidin-1-yl)quinoline;2-(3-(3-(3-chloro-4-ethoxyphenyl)pyrazin-2-yl)azetidin-1-yl)quinoline;2-(3-(3-(3-chloro-4-propoxyphenyl)pyrazin-2-yl)azetidin-1-yl)quinoline;2-(3-(3-(3-fluoro-5-(trifluoromethyl)phenyl)pyrazin-2-yl)azetidin-1-yl)quinoline;2-(3-(3-(4-methoxy-3-methylphenyl)pyrazin-2-yl)azetidin-1-yl)quinoline;2-(3-(3-(3-fluoro-5-isopropoxyphenyl)pyrazin-2-yl)azetidin-1-yl)quinoline;2-(3-(3-(3-fluoro-5-methylphenyl)pyrazin-2-yl)azetidin-1-yl)quinoline;2-(3-(3-(3-chloro-4-fluorophenyl)pyrazin-2-yl)azetidin-1-yl)quinoline;2-(3-(3-(3,4-difluorophenyl)pyrazin-2-yl)azetidin-1-yl)quinoline;2-(3-(3-(3,4-dichlorophenyl)pyrazin-2-yl)azetidin-1-yl)quinoline;2-(3-(3-(3,4-dimethylphenyl)pyrazin-2-yl)azetidin-1-yl)quinoline;2-(3-(3-(3-chloro-4-methylphenyl)pyrazin-2-yl)azetidin-1-yl)quinoline;2-(3-(3-(3-chloro-5-methylphenyl)pyrazin-2-yl)azetidin-1-yl)quinoline;2-(3-(3-(4-fluoro-3-methylphenyl)pyrazin-2-yl)azetidin-1-yl)quinoline;2-(3-(3-(pyrimidin-5-yl)pyrazin-2-yl)azetidin-1-yl)quinoline;2-(3-(3-(4-chloro-3-(trifluoromethyl)phenyl)pyrazin-2-yl)azetidin-1-yl)quinoline;2-(3-(3-(3,6-dihydro-2H-pyran-4-yl)pyrazin-2-yl)azetidin-1-yl)quinoline;2-(3-(3-(2,2-dimethyl-3,6-dihydro-2H-pyran-4-yl)pyrazin-2-yl)azetidin-1-yl)quinoline;2-(3-(3-(6,6-dimethyl-3,6-dihydro-2H-pyran-4-yl)pyrazin-2-yl)azetidin-1-yl)quinoline;2-(3-(3-(1H-pyrazol-4-yl)pyrazin-2-yl)azetidin-1-yl)quinoline;2-(3-(3-(3-fluoro-5-(trifluoromethyl)phenyl)pyrazin-2-yl)azetidin-1-yl)quinoline;2-(3-(3-(6-methoxypyridin-2-yl)pyrazin-2-yl)azetidin-1-yl)quinoline;2-(3-(3-phenylpyrazin-2-yl)azetidin-1-yl)quinoline;2-(3-(3-(4-methoxyphenyl)pyrazin-2-yl)azetidin-1-yl)quinoline;2-(3-(3-(4-fluorophenyl)pyrazin-2-yl)azetidin-1-yl)quinoline;2-(3-(3-(2-fluorophenyl)pyrazin-2-yl)azetidin-1-yl)quinoline;2-(3-(3-(3-fluorophenyl)pyrazin-2-yl)azetidin-1-yl)quinoline;2-(3-(3-(pyridin-4-yl)pyrazin-2-yl)azetidin-1-yl)quinoline;3-(3-(1-(quinolin-2-yl)azetidin-3-yl)pyrazin-2-yl)benzonitrile;4-(3-(1-(quinolin-2-yl)azetidin-3-yl)pyrazin-2-yl)benzonitrile; methyl3-(3-(1-(quinolin-2-yl)azetidin-3-yl)pyrazin-2-yl)benzoate; ethyl4-(3-(1-(quinolin-2-yl)azetidin-3-yl)pyrazin-2-yl)benzoate;2-(3-(3-(2-methoxypyridin-4-yl)pyrazin-2-yl)azetidin-1-yl)quinoline;2-(3-(3-(2-fluoropyridin-4-yl)pyrazin-2-yl)azetidin-1-yl)quinoline;2-(3-(3-(3-(methylthio)phenyl)pyrazin-2-yl)azetidin-1-yl)quinoline;1-(4-(3-(1-(quinolin-2-yl)azetidin-3-yl)pyrazin-2-yl)phenyl)ethanone;2-(3-(3-(4-phenoxyphenyl)pyrazin-2-yl)azetidin-1-yl)quinoline;2-(3-(3-(4-(trifluoromethyl)phenyl)pyrazin-2-yl)azetidin-1-yl)quinoline;2-(3-(3-(3-fluoro-4-methoxyphenyl)pyrazin-2-yl)azetidin-1-yl)quinoline;N,N-dimethyl-3-(3-(1-(quinolin-2-yl)azetidin-3-yl)pyrazin-2-yl)aniline;N-methyl-3-(3-(1-(quinolin-2-yl)azetidin-3-yl)pyrazin-2-yl)benzamide;tert-butyl4-(3-(1-(quinolin-2-yl)azetidin-3-yl)pyrazin-2-yl)-5,6-dihydropyridine-1(2H)-carboxylate;2-(3-(3-([1,1′-biphenyl]-3-yl)pyrazin-2-yl)azetidin-1-yl)quinoline;2-fluoro-4-(3-(1-(quinolin-2-yl)azetidin-3-yl)pyrazin-2-yl)benzonitrile;2-fluoro-5-(3-(1-(quinolin-2-yl)azetidin-3-yl)pyrazin-2-yl)benzonitrile;N,N-dimethyl-3-(3-(1-(quinolin-2-yl)azetidin-3-yl)pyrazin-2-yl)benzamide;2-(3-(3-(2-methoxyphenyl)pyrazin-2-yl)azetidin-1-yl)quinoline;2-(3-(3-(3-(trifluoromethyl)phenyl)pyrazin-2-yl)azetidin-1-yl)quinoline;2-(3-(3-(3-ethoxyphenyl)pyrazin-2-yl)azetidin-1-yl)quinoline;1-(3-(3-(1-(quinolin-2-yl)azetidin-3-yl)pyrazin-2-yl)phenyl)ethanone;(3-(3-(1-(quinolin-2-yl)azetidin-3-yl)pyrazin-2-yl)phenyl)methanol;2-(3-(3-(3-(trifluoromethoxy)phenyl)pyrazin-2-yl)azetidin-1-yl)quinoline;2-(3-(3-(3-(benzyloxy)phenyl)pyrazin-2-yl)azetidin-1-yl)quinoline;N-cyclopropyl-3-(3-(1-(quinolin-2-yl)azetidin-3-yl)pyrazin-2-yl)benzamide;N,N-dimethyl-3-(3-(1-(quinolin-2-yl)azetidin-3-yl)pyrazin-2-yl)benzenesulfonamide;2-(3-(3-(4-ethoxyphenyl)pyrazin-2-yl)azetidin-1-yl)quinoline;(4-(3-(1-(quinolin-2-yl)azetidin-3-yl)pyrazin-2-yl)phenyl)methanol;2-(3-(3-(4-propylphenyl)pyrazin-2-yl)azetidin-1-yl)quinoline;2-(3-(3-(4-ethylphenyl)pyrazin-2-yl)azetidin-1-yl)quinoline;N,N-dimethyl-4-(3-(1-(quinolin-2-yl)azetidin-3-yl)pyrazin-2-yl)aniline;2-(3-(3-(4-(trifluoromethoxy)phenyl)pyrazin-2-yl)azetidin-1-yl)quinoline;2-(3-(3-(4-isopropoxyphenyl)pyrazin-2-yl)azetidin-1-yl)quinoline;2-methyl-2-(4-(3-(1-(quinolin-2-yl)azetidin-3-yl)pyrazin-2-yl)phenyl)propanenitrile;4-((4-(3-(1-(quinolin-2-yl)azetidin-3-yl)pyrazin-2-yl)phenyl)sulfonyl)morpholine;2-(3-(3-(4-(piperidin-1-ylsulfonyl)phenyl)pyrazin-2-yl)azetidin-1-yl)quinoline;(R- &S-)-2-(3-(3-(3-(pyridin-3-yl)pyrrolidin-1-yl)pyrazin-2-yl)azetidin-1-yl)quinoline;(R- &S-)-2-(3-(3-(3-phenethylpyrrolidin-1-yl)pyrazin-2-yl)azetidin-1-yl)quinoline;(R- &S-)-2-(3-(3-(3-benzylpyrrolidin-1-yl)pyrazin-2-yl)azetidin-1-yl)quinoline;(R)—N,N-dimethyl-1-(3-(1-(quinolin-2-yl)azetidin-3-yl)pyrazin-2-yl)pyrrolidin-3-amine;(R- & S-)-tert-butylmethyl(1-(3-(1-(quinolin-2-yl)azetidin-3-yl)pyrazin-2-yl)pyrrolidin-3-yl)carbamate;(R- &S-)-N,N-dimethyl-1-(3-(1-(quinolin-2-yl)azetidin-3-yl)pyrazin-2-yl)pyrrolidin-3-amine;2-(3-(3-(3-azabicyclo[3.1.0]hexan-3-yl)pyrazin-2-yl)azetidin-1-yl)quinoline;(R- &S-)-2-(3-(3-(3-(phenylsulfonyl)pyrrolidin-1-yl)pyrazin-2-yl)azetidin-1-yl)quinoline;(R- &S-)-3-methyl-5-(1-(3-(1-(quinolin-2-yl)azetidin-3-yl)pyrazin-2-yl)pyrrolidin-3-yl)-1,2,4-oxadiazole;(R)-1-(3-(1-(quinolin-2-yl)azetidin-3-yl)pyrazin-2-yl)pyrrolidin-3-ol;(R- &S-)-2-(3-(3-(3-(pyridin-4-yl)pyrrolidin-1-yl)pyrazin-2-yl)azetidin-1-yl)quinoline;2-(3-(3-(pyrrolidin-1-yl)pyrazin-2-yl)azetidin-1-yl)quinoline;(3aR,6aS)-tert-butyl5-(3-(1-(quinolin-2-yl)azetidin-3-yl)pyrazin-2-yl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate;tert-butyl5-(3-(1-(quinolin-2-yl)azetidin-3-yl)pyrazin-2-yl)hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate;tert-butyl4-(3-(1-(quinolin-2-yl)azetidin-3-yl)pyrazin-2-yl)-1,4-diazepane-1-carboxylate;(R)-(1-(3-(1-(quinolin-2-yl)azetidin-3-yl)pyrazin-2-yl)pyrrolidin-3-yl)methanol;(R- &S-)-2-(3-(3-(3-(methylsulfonyl)pyrrolidin-1-yl)pyrazin-2-yl)azetidin-1-yl)quinoline;(S)-(1-(3-(1-(quinolin-2-yl)azetidin-3-yl)pyrazin-2-yl)pyrrolidin-3-yl)methanol;(R)-tert-butyl1-(3-(1-(quinolin-2-yl)azetidin-3-yl)pyrazin-2-yl)pyrrolidin-3-ylcarbamate;(S)-2-(3-(3-(3-fluoropyrrolidin-1-yl)pyrazin-2-yl)azetidin-1-yl)quinoline;2-(3-(3-(3,3-difluoropyrrolidin-1-yl)pyrazin-2-yl)azetidin-1-yl)quinoline;2-(3-(3-(4-isopropyl-1,4-diazepan-1-yl)pyrazin-2-yl)azetidin-1-yl)quinoline;(1R,5R)-3-(3-(1-(quinolin-2-yl)azetidin-3-yl)pyrazin-2-yl)-3-azabicyclo[3.2.2]nonane;2-(3-(3-(azepan-1-yl)pyrazin-2-yl)azetidin-1-yl)quinoline;2-(3-(3-(4-methyl-1,4-diazepan-1-yl)pyrazin-2-yl)azetidin-1-yl)quinoline;3-(3-(1-(quinolin-2-yl)azetidin-3-yl)pyrazin-2-yl)-3-azabicyclo[3.2.2]nonane;1-(4-(3-(1-(quinolin-2-yl)azetidin-3-yl)pyrazin-2-yl)-1,4-diazepan-1-yl)ethanone;(R- &S-)-2-(3-(3-(3-phenylpyrrolidin-1-yl)pyrazin-2-yl)azetidin-1-yl)quinoline;(3S,4S)-1-(3-(1-(quinolin-2-yl)azetidin-3-yl)pyrazin-2-yl)pyrrolidine-3,4-diol;N-(4-methoxybenzyl)-3-(1-(quinolin-2-yl)azetidin-3-yl)pyrazin-2-amine;(1R,4R)-5-(3-(1-(quinolin-2-yl)azetidin-3-yl)pyrazin-2-yl)-2-oxa-5-azabicyclo[2.2.1]heptanes;(R- &S-)-2-(1-(3-(1-(quinolin-2-yl)azetidin-3-yl)pyrazin-2-yl)pyrrolidin-3-yl)thiazole;(S)-(1-(3-(1-(quinolin-2-yl)azetidin-3-yl)pyrazin-2-yl)pyrrolidin-2-yl)methanol;((2S,4S)-4-fluoro-1-(3-(1-(quinolin-2-yl)azetidin-3-yl)pyrazin-2-yl)pyrrolidin-2-yl)methanol;(R)-2-(3-(3-(2-(methoxymethyl)pyrrolidin-1-yl)pyrazin-2-yl)azetidin-1-yl)quinoline;2-(3-(3-(hexahydrocyclopenta[c]pyrrol-2(1H)-yl)pyrazin-2-yl)azetidin-1-yl)quinoline;(R- &S-)-2-(3-(3-(3-isobutylpyrrolidin-1-yl)pyrazin-2-yl)azetidin-1-yl)quinoline;2-(3-(3-(3,3-dimethylpyrrolidin-1-yl)pyrazin-2-yl)azetidin-1-yl)quinoline;(R- &S-)-2-(3-(3-(3-(methoxymethyl)pyrrolidin-1-yl)pyrazin-2-yl)azetidin-1-yl)quinoline;2-(3-(3-(4-(trifluoromethyl)piperidin-1-yl)pyrazin-2-yl)azetidin-1-yl)quinoline;1-(3-(1-(quinolin-2-yl)azetidin-3-yl)pyrazin-2-yl)piperidine-4-carbonitrile;2-(3-(3-(4,4-difluoropiperidin-1-yl)pyrazin-2-yl)azetidin-1-yl)quinoline;4-(3-(1-(quinolin-2-yl)azetidin-3-yl)pyrazin-2-yl)morpholine;2-(3-(3-(4-fluoropiperidin-1-yl)pyrazin-2-yl)azetidin-1-yl)quinoline;2-(3-(3-(3-methoxyazetidin-1-yl)pyrazin-2-yl)azetidin-1-yl)quinoline;2-(3-(3-(3,3-difluoroazetidin-1-yl)pyrazin-2-yl)azetidin-1-yl)quinoline;4-methyl-1-(3-(1-(quinolin-2-yl)azetidin-3-yl)pyrazin-2-yl)piperidin-4-ol;1-(3-(1-(quinolin-2-yl)azetidin-3-yl)pyrazin-2-yl)-1H-pyrazole-4-carbonitrile2-(3-(3-(4-methyl-1H-pyrazol-1-yl)pyrazin-2-yl)azetidin-1-yl)quinoline;tert-butyl(1-(3-(1-(quinolin-2-yl)azetidin-3-yl)pyrazin-2-yl)azetidin-3-yl)carbamate;2,2-dimethyl-4-(3-(1-(quinolin-2-yl)azetidin-3-yl)pyrazin-2-yl)morpholine;2-(3-(3-(4-methyl-1H-imidazol-1-yl)pyrazin-2-yl)azetidin-1-yl)quinoline;1-(3-(1-(quinazolin-2-yl)azetidin-3-yl)pyrazin-2-yl)piperidine-4-carbonitrile;(1-(3-(1-(quinolin-2-yl)azetidin-3-yl)pyrazin-2-yl)-1H-pyrazol-4-yl)methanol;(1-(3-(1-(quinolin-2-yl)azetidin-3-yl)pyrazin-2-yl)-1H-imidazol-4-yl)methanol;1-methyl-4-(3-(1-(quinolin-2-yl)azetidin-3-yl)pyrazin-2-yl)piperazin-2-one;N-(2,6-dimethylphenyl)-1-(3-(1-(quinolin-2-yl)azetidin-3-yl)pyrazin-2-yl)piperidine-3-carboxamide;(S)-tert-butyl(1-(3-(1-(quinolin-2-yl)azetidin-3-yl)pyrazin-2-yl)piperidin-3-yl)carbamate;(4-(cyclopropylmethyl)-1-(3-(1-(quinolin-2-yl)azetidin-3-yl)pyrazin-2-yl)piperidin-4-yl)methanol;2-(3-(3-((1R,5S)-8-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)pyrazin-2-yl)azetidin-1-yl)quinoline;1-(3-(1-(quinolin-2-yl)azetidin-3-yl)pyrazin-2-yl)pyrrolidin-3-amine;(R- & S-)-methyl(1-(3-(1-(quinolin-2-yl)azetidin-3-yl)pyrazin-2-yl)pyrrolidin-3-yl)carbamate;(R- &S-)—N-(1-(3-(1-(quinolin-2-yl)azetidin-3-yl)pyrazin-2-yl)pyrrolidin-3-yl)methanesulfonamide;(R- &S-)-ethyl(1-(3-(1-(quinolin-2-yl)azetidin-3-yl)pyrazin-2-yl)pyrrolidin-3-yl)carbamate;(R- &S-)-2-methoxy-N-(1-(3-(1-(quinolin-2-yl)azetidin-3-yl)pyrazin-2-yl)pyrrolidin-3-yl)acetamide;2-(3-(3-(1,4-Diazepan-1-yl)pyrazin-2-yl)azetidin-1-yl)quinoline; Methyl4-(3-(1-(quinolin-2-yl)azetidin-3-yl)pyrazin-2-yl)-1,4-diazepane-1-carboxylate;methylmethyl(1-(3-(1-(quinolin-2-yl)azetidin-3-yl)pyrazin-2-yl)pyrrolidin-3-yl)carbamate;N-methyl-N-(1-(3-(1-(quinolin-2-yl)azetidin-3-yl)pyrazin-2-yl)pyrrolidin-3-yl)methanesulfonamide;Ethylmethyl(1-(3-(1-(quinolin-2-yl)azetidin-3-yl)pyrazin-2-yl)pyrrolidin-3-yl)carbamate;2-(3-(3-(4-chlorophenyl)pyrazin-2-yl)azetidin-1-yl)quinazoline;2-(3-(3-(3-chlorophenyl)pyrazin-2-yl)azetidin-1-yl)quinazoline;2-(3-(3-(2-chlorophenyl)pyrazin-2-yl)azetidin-1-yl)quinazoline;2-(3-(3-(o-tolyl)pyrazin-2-yl)azetidin-1-yl)quinazoline;1-(4-(3-(1-(quinazolin-2-yl)azetidin-3-yl)pyrazin-2-yl)phenyl)ethanone;1-(3-(3-(1-(quinazolin-2-yl)azetidin-3-yl)pyrazin-2-yl)phenyl)ethanone;N-(3-(3-(1-(quinazolin-2-yl)azetidin-3-yl)pyrazin-2-yl)phenyl)acetamide;N-(4-(3-(1-(quinazolin-2-yl)azetidin-3-yl)pyrazin-2-yl)phenyl)methanesulfonamide;N-(3-(3-(1-(quinazolin-2-yl)azetidin-3-yl)pyrazin-2-yl)phenyl)methanesulfonamide;2-(3-(3-(1H-indol-6-yl)pyrazin-2-yl)azetidin-1-yl)quinazoline;2-(3-(3-(1-methyl-1H-indol-5-yl)pyrazin-2-yl)azetidin-1-yl)quinazoline;2-(3-(3-(1-methyl-1H-indol-6-yl)pyrazin-2-yl)azetidin-1-yl)quinazoline;5-(3-(1-(quinazolin-2-yl)azetidin-3-yl)pyrazin-2-yl)indolin-2-one;1-methyl-5-(3-(1-(quinazolin-2-yl)azetidin-3-yl)pyrazin-2-yl)indolin-2-one;1-methyl-6-(3-(1-(quinazolin-2-yl)azetidin-3-yl)pyrazin-2-yl)-1H-benzo[d]imidazol-2(3H)-one;2-fluoro-4-(3-(1-(quinazolin-2-yl)azetidin-3-yl)pyrazin-2-yl)aniline;2-(3-(3-(p-tolyl)pyrazin-2-yl)azetidin-1-yl)quinazoline;2-methyl-6-(3-(1-(quinazolin-2-yl)azetidin-3-yl)pyrazin-2-yl)isoquinolin-1(2H)-one;2-(3-(3-(1H-indazol-5-yl)pyrazin-2-yl)azetidin-1-yl)quinazoline;5-(3-(1-(quinazolin-2-yl)azetidin-3-yl)pyrazin-2-yl)benzo[d]thiazole; (R&S)-(1H-Benzoimidazol-2-yl)-(3-{3-[4-(1-hydroxy-ethyl)-phenyl]-pyrazin-2-yl}-azetidin-1-yl)-methanone;(R &S)-(1H-Benzoimidazol-2-yl)-(3-{3-[3-(1-hydroxy-ethyl)-phenyl]-pyrazin-2-yl}-azetidin-1-yl)-methanone;(R &S)-(1H-Benzoimidazol-2-yl)-(3-{3-[4-(1-hydroxy-ethyl)-piperidin-1-yl]-pyrazin-2-yl}-azetidin-1-yl)-methanone;1-(4-{3-[1-(1H-Benzoimidazole-2-carbonyl)-azetidin-3-yl]-pyrazin-2-yl}-piperidin-1-yl)-ethanone;1-{3-[1-(1H-Benzoimidazole-2-carbonyl)-azetidin-3-yl]-pyrazin-2-yl}-piperidin-4-one;(1H-Benzoimidazol-2-yl)-{3-[3-(4,4-difluoro-piperidin-1-yl)-pyrazin-2-yl]-azetidin-1-yl}-methanone;(1H-Benzoimidazol-2-yl)-{3-[3-(4-hydroxy-4-methyl-piperidin-1-yl)-pyrazin-2-yl]-azetidin-1-yl}-methanone;(1H-Benzoimidazol-2-yl)-[3-(5-phenyl-pyrimidin-4-yl)-azetidin-1-yl]-methanone;2-(3-(3-(prop-1-yn-1-yl)pyrazin-2-yl)azetidin-1-yl)quinoline;2-[3-(3-m-Tolyl-pyrazin-2-yl)-azetidin-1-yl]-quinoline;2-[3-(3-m-Tolyl-pyrazin-2-yl)-azetidin-1-yl]-quinazoline;2-[3-(3-m-Tolyl-pyrazin-2-yl)-azetidin-1-yl]-quinoxaline;2-[3-(3-m-Tolyl-pyrazin-2-yl)-azetidin-1-yl]-benzothiazole;2-{3-[3-(3-Methoxy-phenyl)-pyrazin-2-yl]-azetidin-1-yl}-quinoline;2-{3-[3-(3-Methoxy-phenyl)-pyrazin-2-yl]-azetidin-1-yl}-quinazoline;2-{3-[3-(3-Methoxy-phenyl)-pyridin-2-yl]-azetidin-1-yl}-quinoline;2-[3-(3-m-Tolyl-pyridin-2-yl)-azetidin-1-yl]-quinoline; (R &S)-2-{3-[3-(3-Methyl-pyrrolidin-1-yl)-pyridin-2-yl]-azetidin-1-yl}-quinoline;4-Methyl-2′-(1-quinolin-2-yl-azetidin-3-yl)-3,4,5,6-tetrahydro-2H-[1,3]bipyridinyl;{1-[3-(1-Quinolin-2-yl-piperidin-4-yl)-pyrazin-2-yl]-piperidin-4-yl}-methanol;{1-[3-(1-Quinolin-2-yl-azetidin-3-yl)-pyrazin-2-yl]-piperidin-4-yl}-methanol;{1-[3-(1-Quinazolin-2-yl-azetidin-3-yl)-pyrazin-2-yl]-piperidin-4-yl}-methanol;4-[3-(1-Quinolin-2-yl-azetidin-3-yl)-pyrazin-2-yl]-phenylamine;{1-[3-(1-Benzothiazol-2-yl-azetidin-3-yl)-pyrazin-2-yl]-piperidin-4-yl}-methanol;{1-[3-(1-Benzooxazol-2-yl-azetidin-3-yl)-pyrazin-2-yl]-piperidin-4-yl-methanol;(1-{3-[1(5-Methyl-pyridin-2-yl)-azetidin-3-yl]-pyrazin-2-yl}-piperidin-4-yl)-quinoline;2-(4-benzylpiperidin-1-yl)-3-(1-(quinolin-2-yl)azetidin-3-yl)quinoxaline;[5′-Fluoro-2′-(1-quinolin-2-yl-azetidin-3-yl)-3,4,5,6-tetrahydro-2H-[1,3′]bipyridinyl-4-yl]-quinoline;{1-[3-(1-Quinolin-2-yl-azetidin-3-yl)-pyridazin-4-yl]-piperidin-4-yl}-quinoline;(R &S)-2-(3-(3-(3-methylpyrrolidin-1-yl)pyrazin-2-yl)azetidin-1-yl)quinoline;(S orR)-2-(3-(3-(3-methylpyrrolidin-1-yl)pyrazin-2-yl)azetidin-1-yl)quinoline;(R orS)-2-(3-(3-(3-methylpyrrolidin-1-yl)pyrazin-2-yl)azetidin-1-yl)quinoline;2-(1-Quinolin-2-yl-azetidin-3-yl)-3-m-tolyl-quinoxaline;4-[3-(1-Quinolin-2-yl-azetidin-3-yl)-quinoxalin-2-yl]-phenylamine;3-[3-(1-Quinolin-2-yl-azetidin-3-yl)-quinoxalin-2-yl]-phenol;2-(3-Methoxy-phenyl)-3-(1-quinolin-2-yl-azetidin-3-yl)-quinoxaline;2-[3-(1-Quinolin-2-yl-azetidin-3-yl)-pyrazin-2-yl]-phenol;3-[3-(1-Quinolin-2-yl-azetidin-3-yl)-pyrazin-2-yl]-phenol;4-[3-(1-Quinolin-2-yl-azetidin-3-yl)-pyrazin-2-yl]-phenol;2-[3-(1-Quinolin-2-yl-azetidin-3-yl)-pyrazin-2-yl]-phenylamine;3-[3-(1-Quinolin-2-yl-azetidin-3-yl)-pyrazin-2-yl]-phenylamine;4-[3-(1-Quinolin-2-yl-azetidin-3-yl)-pyrazin-2-yl]-phenylamine;2-{3-[3-(4-Fluoro-3-methoxy-phenyl)-pyrazin-2-yl]-azetidin-1-yl}-quinoline;2-Fluoro-4-[3-(1-quinolin-2-yl-azetidin-3-yl)-pyrazin-2-yl]-phenylamine2-[3-(3-Piperidin-1-yl-pyrazin-2-yl)-azetidin-1-yl]-quinoline;2-{3-[3-(4-Methyl-piperidin-1-yl)-pyrazin-2-yl]-azetidin-1-yl}-quinoline;1-[3-(1-Quinolin-2-yl-azetidin-3-yl)-pyrazin-2-yl]-piperidine-4-carboxylicacid amide;1-[3-(1-Quinolin-2-yl-azetidin-3-yl)-pyrazin-2-yl]-piperidine-4-carboxylicacid dimethylamide;1-[3-(1-Quinolin-2-yl-azetidin-3-yl)-pyrazin-2-yl]-piperidine-4-carboxylicacid methylamide;1-[3′-(1-Quinolin-2-yl-azetidin-3-yl)-2,3,5,6-tetrahydro-[1,2′]bipyrazinyl-4-yl]-ethanone;1-[3-(1-Quinolin-2-yl-azetidin-3-yl)-pyrazin-2-yl]-piperidin-4-ol;2-Methoxy-1-{4-[3-(1-quinolin-2-yl-azetidin-3-yl)-pyrazin-2-yl]-piperidin-1-yl}-ethanone;1-{4-[3-(1-Quinolin-2-yl-azetidin-3-yl)-pyrazin-2-yl]-piperidin-1-yl}-ethanone;N-{4-[3-(1-Quinolin-2-yl-azetidin-3-yl)-pyrazin-2-yl]-phenyl}-acetamide;1-(4-(3-(1-(quinolin-2-yl)azetidin-3-yl)pyrazin-2-yl)-5,6-dihydropyridin-1(2H)-yl)ethanone;(R &S)-1-{1-[3-(1-Quinolin-2-yl-azetidin-3-yl)-pyrazin-2-yl]-piperidin-4-yl}-ethanol;(R or S, absolute stereospecificity notdetermined)-1-{1-[3-(1-Quinolin-2-yl-azetidin-3-yl)-pyrazin-2-yl]-piperidin-4-yl}-ethanol;(S or R, absolute stereospecificity notdetermined)-1-{1-[3-(1-Quinolin-2-yl-azetidin-3-yl)-pyrazin-2-yl]-piperidin-4-yl}-ethanol;2-fluoro-5-(3-(1-(quinolin-2-yl)azetidin-3-yl)pyrazin-2-yl)phenol;(1-{3-[1-(6-Methyl-quinolin-2-yl)-azetidin-3-yl]-pyrazin-2-yl}-piperidin-4-yl)-quinoline;(1-{3-[1-(7-Fluoro-quinolin-2-yl)-azetidin-3-yl]-pyrazin-2-yl}-piperidin-4-yl)-quinoline;(1-{3-[1-(6-Fluoro-quinolin-2-yl)-azetidin-3-yl]-pyrazin-2-yl}-piperidin-4-yl)-quinoline;{1-[3-(1-[1,8]Naphthyridin-2-yl-azetidin-3-yl)-pyrazin-2-yl]-piperidin-4-yl}-quinoline;(1-{3-[1-(6-Chloro-quinolin-2-yl)-azetidin-3-yl]-pyrazin-2-yl}-piperidin-4-yl)-quinoline;(1-{3-[1-(6-Chloro-quinoxalin-2-yl)-azetidin-3-yl]-pyrazin-2-yl}-piperidin-4-yl)-quinoline;(1-{3-[1-(6-Methyl-pyridin-2-yl)-azetidin-3-yl]-pyrazin-2-yl}-piperidin-4-yl)-quinoline;(1-{3-[1-(5-Chloro-pyridin-2-yl)-azetidin-3-yl]-pyrazin-2-yl}-piperidin-4-yl)-quinoline;(1-(3-(1-(5-bromopyridin-2-yl)azetidin-3-yl)pyrazin-2-yl)piperidin-4-yl)quinoline;(1-(3-(1-(8-methylquinolin-2-yl)azetidin-3-yl)pyrazin-2-yl)piperidin-4-yl)quinoline;(1-{3-[1-(8-Fluoro-quinolin-2-yl)-azetidin-3-yl]-pyrazin-2-yl}-piperidin-4-yl)-quinoline;(1-(3-(1-(8-chloroquinolin-2-yl)azetidin-3-yl)pyrazin-2-yl)piperidin-4-yl)quinoline;(1-{3-[1-(8-Chloro-quinazolin-2-yl)-azetidin-3-yl]-pyrazin-2-yl}-piperidin-4-yl)-quinoline;(1-{3-[1-(7-Chloro-quinazolin-2-yl)-azetidin-3-yl]-pyrazin-2-yl}-piperidin-4-yl)-quinoline;(1-{3-[1-(6-Chloro-quinazolin-2-yl)-azetidin-3-yl]-pyrazin-2-yl}-piperidin-4-yl)-quinoline;(1-{3-[1-(5-Chloro-quinazolin-2-yl)-azetidin-3-yl]-pyrazin-2-yl}-piperidin-4-yl)-quinoline;(1-{3-[1-(7-Chloro-quinoxalin-2-yl)-azetidin-3-yl]-pyrazin-2-yl}-piperidin-4-yl)-quinoline;2-[3-(3-Piperidin-1-yl-pyrazin-2-yl)-azetidin-1-yl]-benzothiazole;2-(3-(3-(3-methoxyphenyl)pyrazin-2-yl)azetidin-1-yl)-8-methylquinoline;6-Chloro-2-{3-[3-(3-methoxy-phenyl)-pyrazin-2-yl]-azetidin-1-yl}-quinazoline8-Chloro-2-{3-[3-(3-methoxy-phenyl)-pyrazin-2-yl]-azetidin-1-yl}-quinoline;7-Fluoro-2-{3-[3-(3-methoxy-phenyl)-pyrazin-2-yl]-azetidin-1-yl}-quinoline;2-{3-[3-(3-Methoxy-phenyl)-pyrazin-2-yl]-azetidin-1-yl}-6-methyl-quinoline;2-{3-[3-(3-Methoxy-phenyl)-pyrazin-2-yl]-azetidin-1-yl}-[1,8]naphthyridine;8-Chloro-2-{3-[3-(3-methoxy-phenyl)-pyrazin-2-yl]-azetidin-1-yl}-quinazoline;5-Chloro-2-{3-[3-(3-methoxy-phenyl)-pyrazin-2-yl]-azetidin-1-yl}-quinazoline;2-(3-(3-(3-methoxyphenyl)pyrazin-2-yl)azetidin-1-yl)-4-phenylpyrimidine;2-(3-(3-(3-methoxyphenyl)pyrazin-2-yl)azetidin-1-yl)benzo[d]thiazole;6-methoxy-2-(3-(3-(3-methoxyphenyl)pyrazin-2-yl)azetidin-1-yl)benzo[d]thiazole;2-(3-(3-(3-methoxyphenyl)pyrazin-2-yl)azetidin-1-yl)-1,6-naphthyridine;6-chloro-2-(3-(3-(3-methoxyphenyl)pyrazin-2-yl)azetidin-1-yl)quinoline;6-fluoro-2-(3-(3-(3-methoxyphenyl)pyrazin-2-yl)azetidin-1-yl)benzo[d]thiazole;2-(3-(3-(3-methoxyphenyl)pyrazin-2-yl)azetidin-1-yl)quinoline;-3-carbonitrile;1-[3-(3-Phenyl-pyrazin-2-yl)-azetidin-1-yl]-phthalazine;6-chloro-2-(3-(3-phenylpyrazin-2-yl)azetidin-1-yl)-1H-benzo[d]imidazole;2-(3-(3-phenylpyrazin-2-yl)azetidin-1-yl)-1H-benzo[d]imidazole;2-((3-(3-phenylpyrazin-2-yl)azetidin-1-yl)methyl)-1H-benzo[d]imidazole;3-(3-(1-(quinolin-2-yl)azetidin-3-yl)pyrazin-2-yl)benzamide;4-(3-(1-(quinolin-2-yl)azetidin-3-yl)pyrazin-2-yl)benzamide;2-fluoro-5-(3-(1-(quinolin-2-yl)azetidin-3-yl)pyrazin-2-yl)benzamide;2-fluoro-4-(3-(1-(quinolin-2-yl)azetidin-3-yl)pyrazin-2-yl)benzamide;2-(3-(3-(1-(quinolin-2-yl)azetidin-3-yl)pyrazin-2-yl)phenyl)propan-2-ol;2-(4-(3-(1-(quinolin-2-yl)azetidin-3-yl)pyrazin-2-yl)phenyl)propan-2-ol;2-(3-(3-(1,2,3,6-tetrahydropyridin-4-yl)pyrazin-2-yl)azetidin-1-yl)quinoline;lithium 3-(3-(1-(quinolin-2-yl)azetidin-3-yl)pyrazin-2-yl)benzoate; (SorR)-2-(3-(3-(3-(pyridin-3-yl)pyrrolidin-1-yl)pyrazin-2-yl)azetidin-1-yl)quinoline;(R orS)-2-(3-(3-(3-(pyridin-3-yl)pyrrolidin-1-yl)pyrazin-2-yl)azetidin-1-yl)quinoline;(1H-Benzoimidazol-2-yl)-{3-[3-(2-methoxy-phenoxy)-pyrazin-2-yl]-azetidin-1-yl}-methanone;(1H-Benzoimidazol-2-yl)-{3-[3-(3-methoxy-phenoxy)-pyrazin-2-yl]-azetidin-1-yl}-methanone;(1H-benzoimidazol-2-yl)-{3-[3-(4-methoxy-phenoxy)-pyrazin-2-yl]-azetidin-1-yl}-methanone;(1H-Benzoimidazol-2-yl)-[3-(3-phenoxy-pyrazin-2-yl)-azetidin-1-yl]-methanone;(1H-benzoimidazol-2-yl)-{3-[3-(tetrahydro-pyran-4-yl)-pyrazin-2-yl]-azetidin-1-yl}-methanone;(7-Chloro-1H-benzoimidazol-2-yl)-[3-(3-phenyl-pyrazin-2-yl)-azetidin-1-yl]-methanone;(6-Chloro-1H-benzoimidazol-2-yl)-[3-(3-phenyl-pyrazin-2-yl)-azetidin-1-yl]-methanone;(7-Fluoro-1H-benzoimidazol-2-yl)-[3-(3-phenyl-pyrazin-2-yl)-azetidin-1-yl]-methanone;(6-Fluoro-1H-benzoimidazol-2-yl)-[3-(3-phenyl-pyrazin-2-yl)-azetidin-1-yl]-methanone;(6-methyl-1H-benzoimidazol-2-yl)-[3-(3-phenyl-pyrazin-2-yl)-azetidin-1-yl]-methanone;(6-methyl-1H-benzoimidazol-2-yl)-[3-(3-phenyl-pyrazin-2-yl)-azetidin-1-yl]-methanone;(1H-benzoimidazol-2-yl)-{3-[3-(2-methoxy-phenyl)-pyrazin-2-yl]-azetidin-1-yl}-methanone;(1H-benzoimidazol-2-yl)-{3-[3-(3-methoxy-phenyl)-pyrazin-2-yl]-azetidin-1-yl}-methanone;(1H-Benzoimidazol-2-yl)-{3-[3-(4-methoxy-phenyl)-pyrazin-2-yl]-azetidin-1-yl}-methanone;(1H-benzoimidazol-2-yl)-[3-(2-phenyl-pyridin-3-yl)-azetidin-1-yl]-methanone;or 2-(3-(3-(1H-indol-5-yl)pyrazin-2-yl)azetidin-1-yl)quinazoline.